Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT00494624 |
| Other study ID # |
VINKU |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 4
|
| First received |
June 29, 2007 |
| Last updated |
June 29, 2007 |
| Start date |
September 2000 |
| Est. completion date |
May 2008 |
Study information
| Verified date |
June 2007 |
| Source |
University of Turku |
| Contact |
Tuomas Jartti, MD |
| Phone |
+358 2 313 0000 |
| Email |
tuomas.jartti[@]utu.fi |
| Is FDA regulated |
No |
| Health authority |
Finland: Finnish Medicines Agency |
| Study type |
Interventional
|
Clinical Trial 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 mg/kg,
then 2 mg/kg/d/3 (max. 60 mg/vrk) p.o. 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.
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 0.05 and a beta error of 0.20, 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 e.g. 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), e.g. 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 mg/kg, then 2 mg/kg/d/3 (max. 60 mg/vrk) p.o. 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 i.v. or i.m. (62,5 mg/ml
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). Guardian’s 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 a.m. and p.m.
The study is outlined in the study flow sheet (Appendix 4). The study physician will examine
the patients twice daily at 8-10 a.m. and p.m. 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 1/3 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 Children’s 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 (0=none, 1=mild, 2=moderate, 3=severe), type of breathing
(0=normal, 1=use of stomach muscles, 2=use of intercostal muscles, 3=nasal flaring),
severity of auscultatory findings on wheezing (0=none, 1=expiratory, 2=inspiratory and
expiratory, 3=audible without stethoscope), and assessment of expiratory:inspiratory time
(0=1:2, 1=1:1, 2=2:1, 3=3:1). An estimation of 6 h will be used for the last 12 h period
between hospital assessments, i.e. 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 (e.g. 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
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