Ignite Creation Date:
2024-05-05 @ 5:36 PM
Last Modification Date:
2024-10-26 @ 9:34 AM
Study NCT ID:
NCT00494624
Status:
UNKNOWN
Last Update Posted:
2007-07-02
First Post:
2007-06-29
Brief Title:
Efficacy of Systemic Glucocorticoid in the Treatment of Wheezing in Children
Sponsor:
University of Turku
Organization:
University of Turku
Study Overview
Official Title:
None
Status:
UNKNOWN
Status Verified Date:
2007-06
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
VINKU
Brief Summary:
We can not predict which wheezing child younger than 3 years of age benefits from systemic glucocorticoid and which one does not It is not known whether the differences in the efficacy are related to the differences in viral etiology atopy immunogical maturity or age of the patient The study aims to answer the following questions 1 What is the viral etiology of acute childhood expiratory wheezing 2 What is the efficacy of prednisolone in relation to age atopy and viral etiology in acute childhood wheezing 3 Does prednisolone treatment increase risk for secundary bacterial infection in acute childhood expiratory wheezing 4 What is the significance of inflammatory markers in predicting the efficacy of systemic steroid or patient outcome in acute childhood expiratory wheezing Study will follow randomized double blind placebo-controlled parallel design Study will start in Septemper 2000 and will be performed at the Department of Pediatrics Turku University Hospital Turku Finland The study population will be 300 hospitalized wheezing children aged 3 months - 15 years Investigational drug will be prednisolone first dose 2 mgkg then 2 mgkgd3 max 60 mgvrk po for 3 d and comparative drug will be placebo tablet similar to investigational drug with the equal dosage The primary outcome will be the time until ready for discharge The study will provide new and important information for the diagnostics treatment disease outcome and prevention of acute childhood expiratory wheezing
Detailed Description:
Introduction
Extensive surveys have shown that 6-20 of children have acute expiratory wheezing 1 2 The lifetime prevalence of wheezing among 12-14-year-old children in the Western countries is 8-19 3 4 The clinical illness is called bronchiolitis when occuring for the first time in infants younger than 12 months 5 When occuring later or recurring beside bronchiolitis a diagnosis of wheezy bronchitis has been used 6 In older children wheezy bronchitis cannot be distinguished from virus-induced-asthma In many countries the first expiratory wheezing attack at the age of 3 years is diagnosed as asthma To some extent bronchiolitis wheezy bronchitis and asthma are expressions of the same pathologic process and at present there are no rigid criteria to separate these three illnessess
Acute bronchiolitis is most commonly caused by respiratory syncytial virus RSV and wheezy bronchitis by rhinovirus infections 6 - 8 Exacerbations of asthma are induced in 80-85 of the cases by viral respiratory infections in children mostly rhinovirus infections 7 9
It is well established that systemic glucocorticoids are the cornerstone in the management of acute asthma 10 However systemic glucocorticoids do not appear to be effective in bronchiolitis in young children 11 Despite the lack of evidence for efficacy glucocorticoids are used up to 60 of patients with RSV bronchiolitis 12
The unfavourable effects of glucocorticoids during viral infections have received increasing attention For example steroids have been found to increase the risk of acute otitis media during rhinovirus infections in children 13 In adults glucocorticoids have increased the titers of rhinovirus and the shedding of the virus from the pharynx 14 15 It may be possible that glucocorticoids increase the severity of some viral respiratory tract infections
Today we can not predict which wheezing child younger than 3 years of age benefits from systemic glucocorticoid and which one does not It is not known whether the differences in the efficacy are related to the differences in viral etiology atopy immunogical maturity or age of the patient
Main Questions
1 What is the viral etiology of acute childhood expiratory wheezing
2 What is the efficacy of prednisolone in relation to age atopy and viral etiology in acute childhood expiratory wheezing
3 Does prednisolone treatment increase risk for secundary bacterial infection in acute childhood expiratory wheezing
4 What is the significance of inflammatory markers in predicting the efficacy of systemic steroid or patient outcome in acute childhood expiratory wheezing
Rationale
The study provides new and important information for the diagnostics treatment disease outcome and prevention of acute childhood expiratory wheezing
Design and setting
Study follows randomized double blind placebo-controlled parallel design Study will start in Septemper 2000 and continue until June 2002 except June and July 2001 The study will be performed at the department of pediatrics Turku University Central Hospital Turku Finland
Subjects
The study population will be 300 patients To allow detection of a 18-h difference half of the average duration of stay in our hospital in the time until ready for discharge between the prednisolone-treated group and the placebo groups with an estimated standard deviation of 24 h and to maintain an alpha error of 005 and a beta error of 020 the required size of the sample is 27 children for each treatment group in RSV bronchiolitis 16 No estimate is available for rhinovirus group If patients are separated to different groups according to eg age or viral infection 108 patients are needed On the other hand to get 31 patients with a viral infection viral infection in 80 of patients with expiratory wheezing and sensitivity of methods 69 49 children are needed in each treatment group to assess different subgroups 196 children 9 17 To take account the variations of epidemics a total of 300 children will be recruited The estimated time to get enough patients which need hospitalization for expiratory wheezing will be 2 years at the department of pediatrics Turku University Central Hospital Turku Finland
Inclusion criteria
age 3 months to 16 years
hospitalization for expiratory wheezing
written informed consent from the parents
Exclusion criteria
Any chronic disease other than allergy or asthma eg heart disease immune deficiency or diabetes
varicella and exposure to varicella if not previously have had it
Systemic glucocorticoid 4 weeks prios to the study
Severe disease that needs treatment in the intensive care unit or oxygen saturation below 92 despite of additional oxygen and frequent salbutamol inhalations
Study drugs
Investigational drug
Prednisolone first dose 2 mgkg then 2 mgkgd3 max 60 mgvrk po for 3 d 5 mg tabletti Prednisolon Leiras Finland
Comparative drug
Placebo tablet similar to investigational drug tablet Leiras will be given with the equal dosage
Addministration of the drug
Tablets will be cut in four pieces which mixt into jelly ot yogurt If the child vomits the drug will be given again after 30 min If the child still vomits he or she will be given equal dose of methylprednisolone or physiologic saline iv or im 625 mgml inject Solomet Orion Finland
Randomization
The randomization will be performed by an independent person not participating in the study According to the randomization each volunteer will be allocated to one treatment Individual number 01 onwards will be assigned
Protocol
The study physician will inform the subject and his or her guardian about the study and gives the subject information Appendix 1 Guardians written informed concent Appendix 2 will be obtained after he or she has got acquainted with the test procedure The subject can withdraw the consent to the study at any time Guardian will be asked to fill the modified ISAAC questionaire Appendix 3 New patients will enter the study at 8-10 am and pm
The study is outlined in the study flow sheet Appendix 4 The study physician will examine the patients twice daily at 8-10 am and pm during the hospitalization Appendix 5 The patients will be hospitalized until he or she does not wheeze or have breathing difficulties After the hospitalization the patients will fill symptom diary for 2 weeks Appendix 6 Follow-up visit will be 2 weeks after the hospitalization and follow-up telephone contact will be 2 months after the hospitalization If the patient had a first wheezing episode he or she will be re-examined 12 months after the study and oscillometric examination will be performed if older than 24 months
Nasal swap virological studies will also be performed to 60 healthy control children at outpatient clinic or surgical department in the Turku University Central Hospital during the study period
Methods
Nasopharyngeal swap samples for virologic studies will be collected with 3 sterile cotton swaps which are dipped through the nostrils against nasal mucosa These samples will be placed in a separate viral transport medium tubes for antigen culture and PCR analysis
Virus culture influenza A and B adeno- RS- parainfluenza type 1 2 and 3 virus was done by using the Ohio strain of HeLa cells and human foreskin fibroplasts according to routine procedure Viral antigens influenza A and B adeno- RS- parainfluenza type 1 2 and 3 virus were detected by time-resolved fluoroimmunoassay with monoclonal antibodies 17 Reverse transcription-PCR assays were used for detection of corona- rhino- entero- RS- influenza A and B as well as human metapneumovirus hMPV The details of methods have been discribed earlier 18 19 Virus-specific serum antibody titers Influenza A and B virus adenovirus parainfluenza type 13 and 2 virus RSV HHV-6 and enterovirus IgG as well as for enterovirus also IgM were determined by enzyme immunoassay EIA using antigen-coated solid phase and horsedish peroxidase conjugated rabbit antihuman IgG Dako Glostrup Denmark Three fold increase in IgG antibody titers was considered positive except four fold increase in RSV IgG antibody titers Enterovirus was also considered positive if virus specific IgM was positive
The influenssa A ja B adeno parainfluenssa type 1 2 and 3 as well as respiratory synsytial virus RSV antigen and culture and rhino- entero- and coronavirus PCR will be performed in the Department of Virology Turku university Finland Human metapneumovirus PCR will be performed in the Department of Virology Erasmus Medical Center Rotterdam The Netherlands RSV A and B as well as Influenza virus A and B PCR will be performed in the National Health Institute Helsinki Finland Viral and bacteral C pneumoniae M pneumoniae S pneumoniae H influenzae ja M catarrhalis will be performed in the National Health Institute Oulu Finland 17
Expiratory nitric oxide will collected bed side with a bag collection system Siemens and analysed within 72 h at the Department of Clinical Physiology Turku University Central Hospital Turku Finland 20 Oscillometric studies will be performed at the Department of Paediatric Turku University Central Hospital Turku Finland Nasal cytokine IL-8 and RANTES measurements will be performed in the Childrens Hospital University of Texas Medical Branch Galveston Texas USA Other laboratory tests will be performed in the Central Laboratory Turku University Central Hospital Turku Finland
Primary endpoint Our primary endpoint will be the time until ready for discharge which will be defined as a duration of respiratory symptoms score 3 during hospital stay The respiratory symptoms score which will be assessed every 12 h during hospitalization will consist of the degree of dyspnea 0none 1mild 2moderate 3severe type of breathing 0normal 1use of stomach muscles 2use of intercostal muscles 3nasal flaring severity of auscultatory findings on wheezing 0none 1expiratory 2inspiratory and expiratory 3audible without stethoscope and assessment of expiratoryinspiratory time 012 111 221 331 An estimation of 6 h will be used for the last 12 h period between hospital assessments ie the period during which the patient became ready for discharge
Secondary endpoints Oxygen saturation during hospital stay wheeze and cough during two weeks after discharge from the hospital assessed each day as none mild moderate or severe readmission to the out-patient clinic or hospital for recurrent wheezing during a two-month period after discharge and blood eosinophil counts at discharge and two weeks later
Adverse events
All adverse events encountered during the study period will be reported on the case record forms The subjects will be urged to report any adverse events immetiately after appearance All adverse events will be grated on a scale form 1 to 3 where 1 mild 2 moderate and 3 severe The investigator will also be requested to judge the causality of each adverse event to the treatment 1 not related 2 possibly related and 3 probably related If serious adverse effects occurs the sponsor shall be notified within 24 h by telephone and subsequently in writing by the investigator All serious adverse events must be reported to national regulatory authorities within 24 hours of occurence
Amendment of protocol
A new approval by the ethics committee has to be obtained before execution of any prospective deviation from the signed protocol
Subject recruitment and information
Before recruitement the guardian will be informed about the aims character and risks of the study using the information text in the Subject Information Appendix 1 After the subject has had sufficient time to acquaint himself with the information text the investigator seeks for his written consent Appendix 2 The original signed consent form will be retained by investigator The investigator is responsible for informing all study team members of sufficient details of the study and the methods to be applied
Ethical aspects
This study follows the recommendations for biomedical research involving human subjects current revision of the Declaration of Helsinki of the World Medical Assembly Prior to initiation of the study the protocol the subject information and the informed consent form will be submitted to and approved by the ethics committee of Turku University Central Hospital
Data management and statistical analysis
The data will be collected in statistical software and the results will be analysed using statistical tests appropriate for parallel design All study correspondence records and documents related to the conduct of the study and the distribution of the investigational drug eg diskettes case record forms concent forms and other pertinent information must be retained by the investigator for a period of at least 15 years
References
1 Ruuskanen O Ogra PL Respiratory syncytial virus Curr Probl Pediatr 19932350-79
2 Martinez FD Wright AL Taussig LM Holmberg CJ Halonen M Morgan WJ Asthma and wheezing in the first six years of life The Group Health Medical Associates N Engl J Med 1995332133-8
3 Habbick BF Pizzichini MM Taylor B Rennie D Senthilselvan A Sears MR Prevalence of asthma rhinitis and eczema among children in 2 Canadian cities the International Study of Asthma and Allergies in Childhood CMAJ 19991601824-8
4 Hesselmar B Aberg B Eriksson B Aberg N Asthma in children prevalence treatment and sensitization Pediatr Allergy Immunol 20001174-9
5 McIntosh K Bronchiolitis and asthma possible common pathogenetic pathways J Allergy Clin Immunol 197657595-604
6 Mertsola J Ziegler T Ruuskanen O Vanto T Koivikko A Halonen P Recurrent wheezy bronchitis and viral respiratory infections Arch Dis Child 199166124-9
7 Rakes GP Arruda E Ingram JM et al Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care IgE and eosinophil analyses Am J Respir Crit Care Med 1999159785-90
8 Glezen PW Greenberg SB Atmar RL Piedra PA Couch RB Impact of respiratory virus infections on persons with chronic underlying conditions JAMA 2000283499-505
9 Johnston SL Pattemore PK Sanderson G et al Community study of the role of viral infections in exacerbations of asthma in 9-11 year old children BMJ 19953101225-9
10 Storr J Barrell E Barry W Lenney W Hatcher G Effect of a single oral dose of prednisolonee in acute childhood asthma Lancet 19871879-82
11 Roosevelt G Sheehan K Grupp Phelan J Tanz RR Listernick R Dexamethasone in bronchiolitis a randomised controlled trial Lancet 1996348292-5
12 Wang EEL Law BJ Boucher FD et al Pediatric investigators collaborative network on infections in Canada PICNIC study of admission and management variation in patients hospitalized with respiratory syncytial viral lower respiratory tract infection J Pediatr 1996129390-5
13 Ruohola A Heikkinen T Waris M Puhakka T Ruuskanen O Intranasal fluticasone propionate does not prevent acute otitis media during viral upper respiratory infection in children J Allergy Clin Immunol 2000106467-71
14 Gustafson LM Proud D Hendley JO Hayden FG Gwaltney JM Jr Oral prednisone therapy in experimental rhinovirus infections J Allergy Clin Immunol 1996971009-14
15 Puhakka T Mäkelä MJ Malmström K et al The common cold effects of intranasal fluticasone propionate treatment J Allergy Clin Immunol 1998101726-31
16 De Boeck K Van der Aa N Van Lierde S Corbeel L Eeckels R Respiratory syncytial virus bronchiolitis a double-blind dexamethasone efficacy study J Pediatr 1997131919-21
17 Mäkelä MJ Puhakka T Ruuskanen O Leinonen M Saikku P Kimpimäki M et al Viruses and bacteria in the etiology of the common cold J Clin Microbiol 1998 36 539 42
18 Halonen P Rocha E Hierholzer J Holloway B Hyypiä T Hurskainen P Pallansch M Detection of enteroviruses and rhinoviruses in clinical specimens by PCR and liquid-phase hybridization J Clin Microbiology 199533648-53
19 van den Hoogen BG de Jong JC Groen J Kuiken T de Groot R Fouchier RA Osterhaus AD A newly discovered human pneumovirus isolated from young children with respiratory tract disease Nat Med 20017719-24
20 American Thoracic Society Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children - 1999 Am J Respir Crit Care Med 1999 160 2104-17
Extensive surveys have shown that 6-20 of children have acute expiratory wheezing 1 2 The lifetime prevalence of wheezing among 12-14-year-old children in the Western countries is 8-19 3 4 The clinical illness is called bronchiolitis when occuring for the first time in infants younger than 12 months 5 When occuring later or recurring beside bronchiolitis a diagnosis of wheezy bronchitis has been used 6 In older children wheezy bronchitis cannot be distinguished from virus-induced-asthma In many countries the first expiratory wheezing attack at the age of 3 years is diagnosed as asthma To some extent bronchiolitis wheezy bronchitis and asthma are expressions of the same pathologic process and at present there are no rigid criteria to separate these three illnessess
Acute bronchiolitis is most commonly caused by respiratory syncytial virus RSV and wheezy bronchitis by rhinovirus infections 6 - 8 Exacerbations of asthma are induced in 80-85 of the cases by viral respiratory infections in children mostly rhinovirus infections 7 9
It is well established that systemic glucocorticoids are the cornerstone in the management of acute asthma 10 However systemic glucocorticoids do not appear to be effective in bronchiolitis in young children 11 Despite the lack of evidence for efficacy glucocorticoids are used up to 60 of patients with RSV bronchiolitis 12
The unfavourable effects of glucocorticoids during viral infections have received increasing attention For example steroids have been found to increase the risk of acute otitis media during rhinovirus infections in children 13 In adults glucocorticoids have increased the titers of rhinovirus and the shedding of the virus from the pharynx 14 15 It may be possible that glucocorticoids increase the severity of some viral respiratory tract infections
Today we can not predict which wheezing child younger than 3 years of age benefits from systemic glucocorticoid and which one does not It is not known whether the differences in the efficacy are related to the differences in viral etiology atopy immunogical maturity or age of the patient
Main Questions
1 What is the viral etiology of acute childhood expiratory wheezing
2 What is the efficacy of prednisolone in relation to age atopy and viral etiology in acute childhood expiratory wheezing
3 Does prednisolone treatment increase risk for secundary bacterial infection in acute childhood expiratory wheezing
4 What is the significance of inflammatory markers in predicting the efficacy of systemic steroid or patient outcome in acute childhood expiratory wheezing
Rationale
The study provides new and important information for the diagnostics treatment disease outcome and prevention of acute childhood expiratory wheezing
Design and setting
Study follows randomized double blind placebo-controlled parallel design Study will start in Septemper 2000 and continue until June 2002 except June and July 2001 The study will be performed at the department of pediatrics Turku University Central Hospital Turku Finland
Subjects
The study population will be 300 patients To allow detection of a 18-h difference half of the average duration of stay in our hospital in the time until ready for discharge between the prednisolone-treated group and the placebo groups with an estimated standard deviation of 24 h and to maintain an alpha error of 005 and a beta error of 020 the required size of the sample is 27 children for each treatment group in RSV bronchiolitis 16 No estimate is available for rhinovirus group If patients are separated to different groups according to eg age or viral infection 108 patients are needed On the other hand to get 31 patients with a viral infection viral infection in 80 of patients with expiratory wheezing and sensitivity of methods 69 49 children are needed in each treatment group to assess different subgroups 196 children 9 17 To take account the variations of epidemics a total of 300 children will be recruited The estimated time to get enough patients which need hospitalization for expiratory wheezing will be 2 years at the department of pediatrics Turku University Central Hospital Turku Finland
Inclusion criteria
age 3 months to 16 years
hospitalization for expiratory wheezing
written informed consent from the parents
Exclusion criteria
Any chronic disease other than allergy or asthma eg heart disease immune deficiency or diabetes
varicella and exposure to varicella if not previously have had it
Systemic glucocorticoid 4 weeks prios to the study
Severe disease that needs treatment in the intensive care unit or oxygen saturation below 92 despite of additional oxygen and frequent salbutamol inhalations
Study drugs
Investigational drug
Prednisolone first dose 2 mgkg then 2 mgkgd3 max 60 mgvrk po for 3 d 5 mg tabletti Prednisolon Leiras Finland
Comparative drug
Placebo tablet similar to investigational drug tablet Leiras will be given with the equal dosage
Addministration of the drug
Tablets will be cut in four pieces which mixt into jelly ot yogurt If the child vomits the drug will be given again after 30 min If the child still vomits he or she will be given equal dose of methylprednisolone or physiologic saline iv or im 625 mgml inject Solomet Orion Finland
Randomization
The randomization will be performed by an independent person not participating in the study According to the randomization each volunteer will be allocated to one treatment Individual number 01 onwards will be assigned
Protocol
The study physician will inform the subject and his or her guardian about the study and gives the subject information Appendix 1 Guardians written informed concent Appendix 2 will be obtained after he or she has got acquainted with the test procedure The subject can withdraw the consent to the study at any time Guardian will be asked to fill the modified ISAAC questionaire Appendix 3 New patients will enter the study at 8-10 am and pm
The study is outlined in the study flow sheet Appendix 4 The study physician will examine the patients twice daily at 8-10 am and pm during the hospitalization Appendix 5 The patients will be hospitalized until he or she does not wheeze or have breathing difficulties After the hospitalization the patients will fill symptom diary for 2 weeks Appendix 6 Follow-up visit will be 2 weeks after the hospitalization and follow-up telephone contact will be 2 months after the hospitalization If the patient had a first wheezing episode he or she will be re-examined 12 months after the study and oscillometric examination will be performed if older than 24 months
Nasal swap virological studies will also be performed to 60 healthy control children at outpatient clinic or surgical department in the Turku University Central Hospital during the study period
Methods
Nasopharyngeal swap samples for virologic studies will be collected with 3 sterile cotton swaps which are dipped through the nostrils against nasal mucosa These samples will be placed in a separate viral transport medium tubes for antigen culture and PCR analysis
Virus culture influenza A and B adeno- RS- parainfluenza type 1 2 and 3 virus was done by using the Ohio strain of HeLa cells and human foreskin fibroplasts according to routine procedure Viral antigens influenza A and B adeno- RS- parainfluenza type 1 2 and 3 virus were detected by time-resolved fluoroimmunoassay with monoclonal antibodies 17 Reverse transcription-PCR assays were used for detection of corona- rhino- entero- RS- influenza A and B as well as human metapneumovirus hMPV The details of methods have been discribed earlier 18 19 Virus-specific serum antibody titers Influenza A and B virus adenovirus parainfluenza type 13 and 2 virus RSV HHV-6 and enterovirus IgG as well as for enterovirus also IgM were determined by enzyme immunoassay EIA using antigen-coated solid phase and horsedish peroxidase conjugated rabbit antihuman IgG Dako Glostrup Denmark Three fold increase in IgG antibody titers was considered positive except four fold increase in RSV IgG antibody titers Enterovirus was also considered positive if virus specific IgM was positive
The influenssa A ja B adeno parainfluenssa type 1 2 and 3 as well as respiratory synsytial virus RSV antigen and culture and rhino- entero- and coronavirus PCR will be performed in the Department of Virology Turku university Finland Human metapneumovirus PCR will be performed in the Department of Virology Erasmus Medical Center Rotterdam The Netherlands RSV A and B as well as Influenza virus A and B PCR will be performed in the National Health Institute Helsinki Finland Viral and bacteral C pneumoniae M pneumoniae S pneumoniae H influenzae ja M catarrhalis will be performed in the National Health Institute Oulu Finland 17
Expiratory nitric oxide will collected bed side with a bag collection system Siemens and analysed within 72 h at the Department of Clinical Physiology Turku University Central Hospital Turku Finland 20 Oscillometric studies will be performed at the Department of Paediatric Turku University Central Hospital Turku Finland Nasal cytokine IL-8 and RANTES measurements will be performed in the Childrens Hospital University of Texas Medical Branch Galveston Texas USA Other laboratory tests will be performed in the Central Laboratory Turku University Central Hospital Turku Finland
Primary endpoint Our primary endpoint will be the time until ready for discharge which will be defined as a duration of respiratory symptoms score 3 during hospital stay The respiratory symptoms score which will be assessed every 12 h during hospitalization will consist of the degree of dyspnea 0none 1mild 2moderate 3severe type of breathing 0normal 1use of stomach muscles 2use of intercostal muscles 3nasal flaring severity of auscultatory findings on wheezing 0none 1expiratory 2inspiratory and expiratory 3audible without stethoscope and assessment of expiratoryinspiratory time 012 111 221 331 An estimation of 6 h will be used for the last 12 h period between hospital assessments ie the period during which the patient became ready for discharge
Secondary endpoints Oxygen saturation during hospital stay wheeze and cough during two weeks after discharge from the hospital assessed each day as none mild moderate or severe readmission to the out-patient clinic or hospital for recurrent wheezing during a two-month period after discharge and blood eosinophil counts at discharge and two weeks later
Adverse events
All adverse events encountered during the study period will be reported on the case record forms The subjects will be urged to report any adverse events immetiately after appearance All adverse events will be grated on a scale form 1 to 3 where 1 mild 2 moderate and 3 severe The investigator will also be requested to judge the causality of each adverse event to the treatment 1 not related 2 possibly related and 3 probably related If serious adverse effects occurs the sponsor shall be notified within 24 h by telephone and subsequently in writing by the investigator All serious adverse events must be reported to national regulatory authorities within 24 hours of occurence
Amendment of protocol
A new approval by the ethics committee has to be obtained before execution of any prospective deviation from the signed protocol
Subject recruitment and information
Before recruitement the guardian will be informed about the aims character and risks of the study using the information text in the Subject Information Appendix 1 After the subject has had sufficient time to acquaint himself with the information text the investigator seeks for his written consent Appendix 2 The original signed consent form will be retained by investigator The investigator is responsible for informing all study team members of sufficient details of the study and the methods to be applied
Ethical aspects
This study follows the recommendations for biomedical research involving human subjects current revision of the Declaration of Helsinki of the World Medical Assembly Prior to initiation of the study the protocol the subject information and the informed consent form will be submitted to and approved by the ethics committee of Turku University Central Hospital
Data management and statistical analysis
The data will be collected in statistical software and the results will be analysed using statistical tests appropriate for parallel design All study correspondence records and documents related to the conduct of the study and the distribution of the investigational drug eg diskettes case record forms concent forms and other pertinent information must be retained by the investigator for a period of at least 15 years
References
1 Ruuskanen O Ogra PL Respiratory syncytial virus Curr Probl Pediatr 19932350-79
2 Martinez FD Wright AL Taussig LM Holmberg CJ Halonen M Morgan WJ Asthma and wheezing in the first six years of life The Group Health Medical Associates N Engl J Med 1995332133-8
3 Habbick BF Pizzichini MM Taylor B Rennie D Senthilselvan A Sears MR Prevalence of asthma rhinitis and eczema among children in 2 Canadian cities the International Study of Asthma and Allergies in Childhood CMAJ 19991601824-8
4 Hesselmar B Aberg B Eriksson B Aberg N Asthma in children prevalence treatment and sensitization Pediatr Allergy Immunol 20001174-9
5 McIntosh K Bronchiolitis and asthma possible common pathogenetic pathways J Allergy Clin Immunol 197657595-604
6 Mertsola J Ziegler T Ruuskanen O Vanto T Koivikko A Halonen P Recurrent wheezy bronchitis and viral respiratory infections Arch Dis Child 199166124-9
7 Rakes GP Arruda E Ingram JM et al Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care IgE and eosinophil analyses Am J Respir Crit Care Med 1999159785-90
8 Glezen PW Greenberg SB Atmar RL Piedra PA Couch RB Impact of respiratory virus infections on persons with chronic underlying conditions JAMA 2000283499-505
9 Johnston SL Pattemore PK Sanderson G et al Community study of the role of viral infections in exacerbations of asthma in 9-11 year old children BMJ 19953101225-9
10 Storr J Barrell E Barry W Lenney W Hatcher G Effect of a single oral dose of prednisolonee in acute childhood asthma Lancet 19871879-82
11 Roosevelt G Sheehan K Grupp Phelan J Tanz RR Listernick R Dexamethasone in bronchiolitis a randomised controlled trial Lancet 1996348292-5
12 Wang EEL Law BJ Boucher FD et al Pediatric investigators collaborative network on infections in Canada PICNIC study of admission and management variation in patients hospitalized with respiratory syncytial viral lower respiratory tract infection J Pediatr 1996129390-5
13 Ruohola A Heikkinen T Waris M Puhakka T Ruuskanen O Intranasal fluticasone propionate does not prevent acute otitis media during viral upper respiratory infection in children J Allergy Clin Immunol 2000106467-71
14 Gustafson LM Proud D Hendley JO Hayden FG Gwaltney JM Jr Oral prednisone therapy in experimental rhinovirus infections J Allergy Clin Immunol 1996971009-14
15 Puhakka T Mäkelä MJ Malmström K et al The common cold effects of intranasal fluticasone propionate treatment J Allergy Clin Immunol 1998101726-31
16 De Boeck K Van der Aa N Van Lierde S Corbeel L Eeckels R Respiratory syncytial virus bronchiolitis a double-blind dexamethasone efficacy study J Pediatr 1997131919-21
17 Mäkelä MJ Puhakka T Ruuskanen O Leinonen M Saikku P Kimpimäki M et al Viruses and bacteria in the etiology of the common cold J Clin Microbiol 1998 36 539 42
18 Halonen P Rocha E Hierholzer J Holloway B Hyypiä T Hurskainen P Pallansch M Detection of enteroviruses and rhinoviruses in clinical specimens by PCR and liquid-phase hybridization J Clin Microbiology 199533648-53
19 van den Hoogen BG de Jong JC Groen J Kuiken T de Groot R Fouchier RA Osterhaus AD A newly discovered human pneumovirus isolated from young children with respiratory tract disease Nat Med 20017719-24
20 American Thoracic Society Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children - 1999 Am J Respir Crit Care Med 1999 160 2104-17
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None