Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT00407394 |
Other study ID # |
9998 |
Secondary ID |
|
Status |
Completed |
Phase |
Phase 3
|
First received |
December 2, 2006 |
Last updated |
December 2, 2006 |
Start date |
April 2004 |
Est. completion date |
April 2006 |
Study information
Verified date |
December 2006 |
Source |
King George's Medical University |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
India: Institutional Review Board |
Study type |
Interventional
|
Clinical Trial Summary
Background: The current Integrated management of childhood infections (IMCI) algorithm
prescribes that children with wheeze and fast breathing presenting to first level health
facilities are given antibiotics if they continue to have fast breathing after two doses of
bronchodilator. The primary purpose of the algorithm is to prevent mortality due to
bacterial pneumonia. However, an unknown proportion of children managed in this fashion will
have a viral related wheezing illness or asthma rather than pneumonia. Although it is
unlikely that wheezing syndromes are a significant cause of mortality for children in
developing countries, these algorithms are likely to result in unnecessary administration of
antibiotics as well as inadequate treatment of recurrent wheezing illness. We do not have
clear evidence about whether antibiotics can be withheld in some categories of children with
wheeze. It is clear that wheeze can occur in bacterial infection and in addition
co-infection with virus and bacteria has been well demonstrated in several studies of
pneumonia etiology in children. Although some studies have found that children with more
severe disease or who are blood culture positive are more likely to be febrile at
presentation, this sign is not sufficiently sensitive or specific to determine whether
antibiotics should be administeredSetting: The study will be conducted in eight medical
colleges situated in Lucknow, Nagpur, New Delhi, Mumbai, Chennai, Trivandrum, Vellore, and
Chandigarh. Design: This will be a multicentric, randomized, double blind efficacy trial. .
Hypothesis: The primary hypothesis is that the use of oral amoxycillin for three days would
be as effective, in terms of clinical cure on day 4 as compared to use of oral placeboMain
objective: To compare the proportion of children aged 2 to 59 months presenting with
non-severe pneumonia with wheeze whose respiratory rate does not fall below the age specific
cut-off after three doses of nebulized salbutamol, that achieve clinical cure on day 4 on 3
day of treatment with oral amoxycillin versus placebo.Inclusion criteria: Children aged 2-59
months with non-severe pneumonia based on WHO criteria of respiratory rate above the age
specific cut-off, audible / ausculatory wheeze. Exclusion criteria: Children with severe
disease, received any documented antibiotic treatment in the past 48 hours, diagnosed
asthmatic on maintenance therapy, complicating acute non-pulmonary or chronic illness, known
drug allergy, hospitalization in the past 2 weeks, history of measles within the last month,
known immunodeficiency disorder, prior enrollment in the study, residing in areas not
accessible for follow-up or whose guardian refuses to consent for the study. Sample size:
Has been calculated to test the null hypothesis. There will be 950 children in each arm.
Thus each site is required to recruit a minimum of 225 cases over 18 months.
Description:
Background: The World Health Organizations acute lower respiratory infections (ALRI)
management algorithms depend primarily on two key clinical signs: elevated respiratory rate
and chest indrawing. The current Integrated management of childhood infections (IMCI)
algorithm prescribes that children with wheeze and fast breathing presenting to first level
health facilities are given antibiotics if they continue to have fast breathing after two
doses of bronchodilator. The primary purpose of the algorithm is to prevent mortality due to
bacterial pneumonia. However, an unknown proportion of children managed in this fashion will
have a viral related wheezing illness or asthma rather than pneumonia. Although it is
unlikely that wheezing syndromes are a significant cause of mortality for children in
developing countries, these algorithms are likely to result in unnecessary administration of
antibiotics as well as inadequate treatment of recurrent wheezing illness. In both developed
and developing countries respiratory syncytial virus is the predominant etiological agent
responsible for bronchiolitis and wheezing illness in the first two years of life. Moreover
data from several studies demonstrates that respiratory syncitial virus (RSV) infection and
the bronchiolitis syndrome are a major component of the total ALRI in children living in
developing countries. The relevant literature on therapy includes studies in which children
were labelled as bronchiolitis and others in which children were classified as wheezing
illness.We do not have clear evidence about whether antibiotics can be withheld in some
categories of children with wheeze. It is clear that wheeze can occur in bacterial infection
and in addition co-infection with virus and bacteria has been well demonstrated in several
studies of pneumonia etiology in children. Although some studies have found that children
with more severe disease or who are blood culture positive are more likely to be febrile at
presentation, this sign is not sufficiently sensitive or specific to determine whether
antibiotics should be administered.There has been extensive debate about whether infants and
young children in the first year of life respond to bronchodilator therapy. Proposed reasons
for a lack of response have included: immaturity of bronchiolar smooth muscle, increased
dynamic airway closure and relatively larger degrees of mucosal edema. A literature search
between 1980 and 2000 reveals five randomized placebo controlled trials of beta agonist
administered to acutely wheezing infants in which clinical outcomes were determined. Overall
these studies support the hypothesis that children aged less than 12 to 18 months are less
responsive to bronchodilator therapy than older children. However, they also demonstrate
that use of inhaled short acting bronchodilators for the acute treatment of wheeze offers
some benefits for clinical outcomes even in this young age group. The benefits of beta
agonists may be restricted to children with recurrent wheezing and at most provide a very
small clinical benefitSetting: The study will be conducted in eight medical colleges
situated in New Delhi, Chandigarh, Lucknow, Mumbai, Nagpur, Chennai, Vellore and Trivandrum.
Design: This will be a multicentric, randomized, double blind efficacy trial. Block
randomization will be done in Dept. of Pharmacology, KGMU, Lucknow, which is not the
coordinating center for the trial. Blocks will be generated in mixed batches. The medicines
will be then placed in by the pharmacy according to the intervention type determined by the
pharmacy. Two hundred and twenty five random numbers will be generated in blocks of varying
lengths for each of the nine sites.OutcomesPrimary: Clinical Cure: Respiratory rate below
agerate below ages specific cut-off (<50 bpm in infants <1 year and <40 bpm in ages 12 – 59
months) and absence of auscultatory as well as audible wheeze.Secondary: Response to
nebulization: Respiratory rate below age specific cut-off (<50 bpm in infants <1 year and
<40 bpm in ages 12 – 59 months) after a maximum of three doses of nebuliaztion with
salbutamol, auscultaroy wheeze may or may not be present. But there is no audible
wheeze.Clinical failure of therapy: Any signs of severe pneumonia or severe disease; chest
in drawing, convulsions, drowsiness or inability to drink at any time; Respiratory rate
above age specific cut-off on day 4 or after that (with or without wheeze);Oxygen saturation
on pulse oximetry <90% on day 4 or after that; Documented axillary temperature > 101 degrees
Fahrenheit. In addition, children who die within the follow-up period of 14 days or are lost
to follow-up on day 4 will also be considered as failed.Clinical relapse at day 7- 15: Signs
of severe pneumonia or very severe disease among cases who were clinically cured on day 4
follow-up.Hypothesis: The primary hypothesis is that the use of oral amoxycillin for three
days would be as effective, in terms of clinical cure on day 4 as compared to use of oral
placebo. Intervention: Amoxycillin tablets (125 mg) or placebo They will be used after
dissolving in 5 ml of clean water. The medicines will be given according to the weight of
the child as follows:q 4 – 6 KG ½ tablet thrice a dayq 7 - 10 KG 1 tablet thrice a dayq 11 –
15 KG 1 ½ tablet thrice a dayq 16 – 20 KG 2 tablets thrice a dayMain objective: To compare
the proportion of children aged 2 to 59 months presenting with non-severe pneumonia with
wheeze whose respiratory rate does not fall below the age specific cut-off after three doses
of nebulized salbutamol, that achieve clinical cure on day 4 on 3 day of treatment with oral
amoxycillin versus placeboSecondary objectives: Among all cases of non-severe pneumonia with
wheeze1. To assess the proportion of children aged 2 to 59 months presenting with non-severe
pneumonia with wheezing audible wheeze2. To assess the proportion of children aged 2 to 59
months presenting with non-severe pneumonia with wheezing who respond to up to three doses
of nebulization with salbutamol.Among cases of non-severe pneumonia with wheeze aged 2 to 59
months who respond to three doses of salbutamol3. To assess the proportion of who fail
therapy at day 4 of the initial successful bronchodilator therapy with inhaled salbutamol.4.
To assess the proportion relapse at day 11- 14 of the initial successful bronchodilator
therapy with inhaled salbutamol.5.To compare the cost of treatment of clinical failures and
relapses among those treated with oral salbutamol.6 .To assess the association of
bronchodilator response with age, season, number of previous wheezing episodes, audible
versus auscultatory wheeze and family history of asthma.7.To assess the association of
relapse in children who showed improvement after being treated with inhaled salbutamol, with
age, respiratory syncytial virus (RSV) isolation, season, number of previous wheezing
episodes, audible versus auscultatory wheeze and family history of asthma.Among cases of
non-severe pneumonia with wheeze aged 2 to 59 months who do not respond to three doses of
salbutamol8.To compare the proportion of children who are judged to be clinically cured
after 3 days of treatment but who relapse within the next 11-14 days observation on 3-day
treatment with oral amoxycillin versus placebo.9.To compare the cost of treatment of
clinical failures and relapses among those treated with oral amoxycillin or placebo.10. To
assess the association of clinical failure on day 4 with age, respiratory syncytial virus
(RSV) isolation, season, number of previous wheezing episodes, audible versus auscultatory
wheeze, family history of asthma and randomization to amoxycillin therapy.Inclusion
criteria: Children aged 2-59 months with non-severe pneumonia based on WHO criteria of
respiratory rate above the age specific cut-off, audible / ausculatory wheeze, accessible to
follow up, whose guardians give written informed consent.Exclusion criteria: Children with
severe disease, received any documented antibiotic treatment in the past 48 hours, diagnosed
asthmatic on maintenance therapy, complicating acute non-pulmonary or chronic illness, known
drug allergy, hospitalization in the past 2 weeks, measles or history of measles within the
last month, known immunodeficiency disorder, prior enrollment in the study, residing in
areas not accessible for follow-up or whose guardian refuses to consent for the study.
Radiological Pneumonia on X-Ray.Sample size: Two modes of therapies will be assumed to be
equal if the failure rate in new regimen is not more than 17%. So each site will be required
to recruit and follow up 225 cases in each arm over 18 months. Thus there will be 950
children in each arm.Policy relevance: The present study plans to evaluate the role of
antibiotic in children with non-severe pneumonia presenting with wheeze. It will define the
patient and disease characteristics associated with clinical failure and the need for
antibiotics. The results of the study will formulate policy to use antibiotics in children
with non-severe pneumonia and wheeze.