Ignite Creation Date:
2024-05-05 @ 11:47 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00130013
Status:
COMPLETED
Last Update Posted:
2005-09-23
First Post:
2005-08-12
Brief Title:
Efficacy of Single Versus Double Dose of Oral Amoxicillin for Non-Severe Pneumonia in Children
Sponsor:
ARI Research Cell
Organization:
ARI Research Cell
Study Overview
Official Title:
Comparison of Standard Versus Double Dose of Amoxicillin in the Treatment of Non-Severe Pneumonia in Children Aged 2-59 Months A Multi-Centre Randomized Double Blind Controlled Trial in Pakistan
Status:
COMPLETED
Status Verified Date:
2004-07
Last Known Status:
None
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:
None
Brief Summary:
The World Health Organizations WHO standard case management strategy for reducing acute respiratory infection ARI related mortality recommends oral cotrimoxazole and oral amoxicillin as first line drugs for the treatment of pneumonia In 1989 the Pakistan Ministry of Health MOH adopted this strategy to control ARI mortality and recommended cotrimoxazole for treatment of outpatients pneumonia due to lower costs A number of studies subsequently performed have shown significant in vivo and in vitro resistance of H influenzae and S pneumoniae the commonest bacteria causing childhood pneumonia to cotrimoxazole
Although on a case by case basis for pneumonia in vitro resistance does not correlate very well with in vivo failures nevertheless clinical failure rate for pneumonia therapy has increased in Pakistan over the years One can hypothesize that if bacterial pneumonia is a certain proportion of all pneumonia cases the rise in clinical failures may be related to increasing antimicrobial resistance Therefore it is probable that this rising clinical failure rate could be a reflection of increasing resistance There may be an increase in antimicrobial resistance of S pneumoniae and H influenzae to amoxicillin over the period of years and the rising treatment failure could be a reflection of the rising minimum inhibitory concentrations MICs 2 mcgml for H influenzae 1993-94 thereby resulting in this increasing failure rate
For the current study the researchers propose a multicentre randomized controlled double blind trial in which standard versus double dose oral amoxicillin for three days for the treatment of non-severe pneumonia in children less than five years of age will be compared
Primary Objective
To compare the proportion of children 2 - 59 months of age presenting with non-severe pneumonia who achieve clinical resolution on day 5 with standard 15 mgkg8hrly versus double dose 30 mgkg8hrly of oral amoxicillin therapy given for 3 days
Secondary Objective
To follow the clinical course of non-severe pneumonia with the alternative criteria of treatment failure signs of deterioration ie lower chest indrawing and appearance of danger signs on or before day 3 and compare them with other children who have persistent fast breathing respiratory rate above the cut off for age on day 3
Hypothesis
Therapy outcome with double dose of oral amoxicillin is not different than the standard dose of amoxicillin when used for three days for the treatment of non-severe pneumonia in 2-59 months old children
Although on a case by case basis for pneumonia in vitro resistance does not correlate very well with in vivo failures nevertheless clinical failure rate for pneumonia therapy has increased in Pakistan over the years One can hypothesize that if bacterial pneumonia is a certain proportion of all pneumonia cases the rise in clinical failures may be related to increasing antimicrobial resistance Therefore it is probable that this rising clinical failure rate could be a reflection of increasing resistance There may be an increase in antimicrobial resistance of S pneumoniae and H influenzae to amoxicillin over the period of years and the rising treatment failure could be a reflection of the rising minimum inhibitory concentrations MICs 2 mcgml for H influenzae 1993-94 thereby resulting in this increasing failure rate
For the current study the researchers propose a multicentre randomized controlled double blind trial in which standard versus double dose oral amoxicillin for three days for the treatment of non-severe pneumonia in children less than five years of age will be compared
Primary Objective
To compare the proportion of children 2 - 59 months of age presenting with non-severe pneumonia who achieve clinical resolution on day 5 with standard 15 mgkg8hrly versus double dose 30 mgkg8hrly of oral amoxicillin therapy given for 3 days
Secondary Objective
To follow the clinical course of non-severe pneumonia with the alternative criteria of treatment failure signs of deterioration ie lower chest indrawing and appearance of danger signs on or before day 3 and compare them with other children who have persistent fast breathing respiratory rate above the cut off for age on day 3
Hypothesis
Therapy outcome with double dose of oral amoxicillin is not different than the standard dose of amoxicillin when used for three days for the treatment of non-severe pneumonia in 2-59 months old children
Detailed Description:
INTRODUCTION
World Health Organizations WHO standard case management strategy for reducing ARI related mortality recommends oral cotrimoxazole and oral amoxicillin as first line drugs for the treatment of pneumonia In 1989 the Pakistan Ministry of Health MOH adopted this strategy to control ARI mortality and recommended cotrimoxazole for treatment of outpatients pneumonia due to lower costs A number of studies subsequently performed have shown significant in vivo and in vitro resistance of H influenzae and S pneumoniae the commonest bacteria causing childhood pneumonia to cotrimoxazole
This increase in clinical failure with oral cotrimoxazole has put a lot of pressure both at national and international forums on the National ARI Control Programme of Pakistan to change its recommendations from cotrimoxazole to amoxicillin as the first line of therapy Besides being efficacious for non-severe pneumonia amoxicillin has shown good efficacy in children with severe pneumonia and bacteremic children
Although on a case by case basis for pneumonia in vitro resistance does not correlate very well with in vivo failures one can hypothesize that if bacterial pneumonia is a certain proportion of all pneumonia cases the rise in clinical failures may be related to increasing antimicrobial resistance of S pneumoniae and H influenzae to amoxicillin
It is felt that WHO criteria for treatment failure are too stringent Improvement is defined as the return of respiratory rate to below the cut off for that particular age at 48 hours Some of the children with viral pneumonia will continue to have respiratory rate above the cut off on the first follow-up These children are otherwise well and show no signs of deterioration of the disease but according to WHO criteria they would be classified as treatment failure The treatment failure rates hence are influenced by the definitions used
The existing data shows that if the dose of amoxicillin is increased to achieve higher MICs then the eradication of causative organism tend to be much more complete As yet no clinical trial has been conducted to address this important question in the treatment of childhood pneumonia
The researchers propose a multicentre randomized controlled double blind trial in which standard versus double dose oral amoxicillin for three days for the treatment of non-severe pneumonia in children less than five years of age will be compared
Primary Objectives
1 To compare the proportion of children 2 - 59 months of age presenting with non-severe pneumonia who achieve clinical resolution on day 5 with standard 15 mgkg8hrly versus double dose 30 mgkg8hrly of oral amoxicillin therapy given for 3 days
Secondary Objective
To follow the clinical course of non-severe pneumonia with the alternative criteria of treatment failure signs of deterioration ie lower chest indrawing and appearance of danger signs on or before day 3 and compare them with other children who have persistent fast breathing respiratory rate above the cut off for age on day 3
Null Hypothesis
Therapy outcome with double dose of oral amoxicillin is not different than the standard dose of amoxicillin when used for three days for the treatment of non-severe pneumonia in 2-59 months old children
STUDY POPULATION AND SITE
Patients
They will be recruited from those coming to outpatient departments OPD in large tertiary care hospitals in Pakistan
CONSENT
The purpose of the study will be explained to parents and oral informed consent to participate obtained
Laboratory Workup
Chest radiographs will be taken for all enrolled patients
Study Design
This will be a randomized double blind multi-centre trial
Definitions
ARI is defined according to the WHO ARI Programme guidelines 2 for children who have either a cough or difficult breathing
A clinical resolution is defined as return of respiratory rate to normal no pneumonia according to WHO ARI standard case management classification 2
Clinical Failure is defined as development of chest indrawing or any other danger sign or persistence of fast breathing at day 5 follow-up or thereafter leading to therapy change
Improved will be defined as slower respiratory rate either back to normal range for age or lower by more than 5 compared to previous evaluation feeding better according to mother and lower body temperature than previous assessment
Same will be defined as still breathing fast respiratory rate 5 breathsminute compared to previous evaluation or higher than that with no chest indrawing and or danger sign
Worse will be defined as development of lower chest indrawing or any danger sign
A relapse is defined as development of recurrence signs of pneumonia till day 14 after fast breathing has disappeared initially
Follow-up
All children will be followed-up on day 3 5 and 14
Sample size
Keeping in mind the overall treatment failure rate of 209 with amoxicillin from the MASCOT study 1999 - 2001 it is expected that the proportion of patients who will fail to respond with standard dose amoxicillin will be around 2107 In order for double dose to be more efficacious there should be a difference of more than 5 in the treatment success rate as compared to the standard dose The researchers assume that the failure rate will not be more than 13 with double dose amoxicillin By using the power of 80 and the confidence interval of 95 the estimated sample size comes to 369 for each group Assuming the loss to follow up to be 15 as it is an out patient study and having day 14 follow-up the estimated sample size will be 425 patients in each group a total of 850 patients Thus 900 patients will be enrolled in one and a half ARI season
ADVERSE REACTIONS
Antibiotics such as amoxicillin are generally well tolerated and are rarely associated with serious or life threatening adverse reactions possibly or probably related to drug therapy The most common side effects reported include
Allergic - skin rash hives itching or wheezing Digestive - nausea vomiting diarrhea Metabolic - moderate or transient increase in liver function tests - transaminases Hematological - anemia leucopenia and irreversible thrombocytopenia
Rare side effects include anaphylactic shock Stevens- Johnson syndrome and pseudomembranous colitis
Identifying managing and reporting adverse events
The site investigator will carefully monitor each child for adverse events If an adverse event occurs the site investigator will assess its duration seriousness intensity and relationship to the duration of study medication amoxicillin The principal investigator will use their judgement about whether to continue the child in the study or to discontinue enrollment The event and its treatment will be noted on appropriate CRFs and reported to the DSMC
DATA ENTRY AND ANALYSIS
Data forms will all be filled on auto copy forms and will be reviewed by the site co-ordinator
Data will be entered using Epi Info 6 and will be entered twice by two separate operators and both data bases will be validated using Epi Info 6
Outcome measures
A clinical resolution is defined as return of respiratory rate to normal no pneumonia on day 5 according to WHO ARI standard case management classification
Clinicaltreatment Failure is defined as development of chest indrawing or any other danger sign or persistence of fast breathing at day 5 follow-up or thereafter leading to therapy change
Data analysis
Analysis will be carried out on intention to treat basis For primary outcome proportion of therapy failures and their 95 CI will be calculated for both the two regimens Then the researchers will compare proportion of therapy failure using alternative criteria and WHO defined conventional therapy failure criteria
World Health Organizations WHO standard case management strategy for reducing ARI related mortality recommends oral cotrimoxazole and oral amoxicillin as first line drugs for the treatment of pneumonia In 1989 the Pakistan Ministry of Health MOH adopted this strategy to control ARI mortality and recommended cotrimoxazole for treatment of outpatients pneumonia due to lower costs A number of studies subsequently performed have shown significant in vivo and in vitro resistance of H influenzae and S pneumoniae the commonest bacteria causing childhood pneumonia to cotrimoxazole
This increase in clinical failure with oral cotrimoxazole has put a lot of pressure both at national and international forums on the National ARI Control Programme of Pakistan to change its recommendations from cotrimoxazole to amoxicillin as the first line of therapy Besides being efficacious for non-severe pneumonia amoxicillin has shown good efficacy in children with severe pneumonia and bacteremic children
Although on a case by case basis for pneumonia in vitro resistance does not correlate very well with in vivo failures one can hypothesize that if bacterial pneumonia is a certain proportion of all pneumonia cases the rise in clinical failures may be related to increasing antimicrobial resistance of S pneumoniae and H influenzae to amoxicillin
It is felt that WHO criteria for treatment failure are too stringent Improvement is defined as the return of respiratory rate to below the cut off for that particular age at 48 hours Some of the children with viral pneumonia will continue to have respiratory rate above the cut off on the first follow-up These children are otherwise well and show no signs of deterioration of the disease but according to WHO criteria they would be classified as treatment failure The treatment failure rates hence are influenced by the definitions used
The existing data shows that if the dose of amoxicillin is increased to achieve higher MICs then the eradication of causative organism tend to be much more complete As yet no clinical trial has been conducted to address this important question in the treatment of childhood pneumonia
The researchers propose a multicentre randomized controlled double blind trial in which standard versus double dose oral amoxicillin for three days for the treatment of non-severe pneumonia in children less than five years of age will be compared
Primary Objectives
1 To compare the proportion of children 2 - 59 months of age presenting with non-severe pneumonia who achieve clinical resolution on day 5 with standard 15 mgkg8hrly versus double dose 30 mgkg8hrly of oral amoxicillin therapy given for 3 days
Secondary Objective
To follow the clinical course of non-severe pneumonia with the alternative criteria of treatment failure signs of deterioration ie lower chest indrawing and appearance of danger signs on or before day 3 and compare them with other children who have persistent fast breathing respiratory rate above the cut off for age on day 3
Null Hypothesis
Therapy outcome with double dose of oral amoxicillin is not different than the standard dose of amoxicillin when used for three days for the treatment of non-severe pneumonia in 2-59 months old children
STUDY POPULATION AND SITE
Patients
They will be recruited from those coming to outpatient departments OPD in large tertiary care hospitals in Pakistan
CONSENT
The purpose of the study will be explained to parents and oral informed consent to participate obtained
Laboratory Workup
Chest radiographs will be taken for all enrolled patients
Study Design
This will be a randomized double blind multi-centre trial
Definitions
ARI is defined according to the WHO ARI Programme guidelines 2 for children who have either a cough or difficult breathing
A clinical resolution is defined as return of respiratory rate to normal no pneumonia according to WHO ARI standard case management classification 2
Clinical Failure is defined as development of chest indrawing or any other danger sign or persistence of fast breathing at day 5 follow-up or thereafter leading to therapy change
Improved will be defined as slower respiratory rate either back to normal range for age or lower by more than 5 compared to previous evaluation feeding better according to mother and lower body temperature than previous assessment
Same will be defined as still breathing fast respiratory rate 5 breathsminute compared to previous evaluation or higher than that with no chest indrawing and or danger sign
Worse will be defined as development of lower chest indrawing or any danger sign
A relapse is defined as development of recurrence signs of pneumonia till day 14 after fast breathing has disappeared initially
Follow-up
All children will be followed-up on day 3 5 and 14
Sample size
Keeping in mind the overall treatment failure rate of 209 with amoxicillin from the MASCOT study 1999 - 2001 it is expected that the proportion of patients who will fail to respond with standard dose amoxicillin will be around 2107 In order for double dose to be more efficacious there should be a difference of more than 5 in the treatment success rate as compared to the standard dose The researchers assume that the failure rate will not be more than 13 with double dose amoxicillin By using the power of 80 and the confidence interval of 95 the estimated sample size comes to 369 for each group Assuming the loss to follow up to be 15 as it is an out patient study and having day 14 follow-up the estimated sample size will be 425 patients in each group a total of 850 patients Thus 900 patients will be enrolled in one and a half ARI season
ADVERSE REACTIONS
Antibiotics such as amoxicillin are generally well tolerated and are rarely associated with serious or life threatening adverse reactions possibly or probably related to drug therapy The most common side effects reported include
Allergic - skin rash hives itching or wheezing Digestive - nausea vomiting diarrhea Metabolic - moderate or transient increase in liver function tests - transaminases Hematological - anemia leucopenia and irreversible thrombocytopenia
Rare side effects include anaphylactic shock Stevens- Johnson syndrome and pseudomembranous colitis
Identifying managing and reporting adverse events
The site investigator will carefully monitor each child for adverse events If an adverse event occurs the site investigator will assess its duration seriousness intensity and relationship to the duration of study medication amoxicillin The principal investigator will use their judgement about whether to continue the child in the study or to discontinue enrollment The event and its treatment will be noted on appropriate CRFs and reported to the DSMC
DATA ENTRY AND ANALYSIS
Data forms will all be filled on auto copy forms and will be reviewed by the site co-ordinator
Data will be entered using Epi Info 6 and will be entered twice by two separate operators and both data bases will be validated using Epi Info 6
Outcome measures
A clinical resolution is defined as return of respiratory rate to normal no pneumonia on day 5 according to WHO ARI standard case management classification
Clinicaltreatment Failure is defined as development of chest indrawing or any other danger sign or persistence of fast breathing at day 5 follow-up or thereafter leading to therapy change
Data analysis
Analysis will be carried out on intention to treat basis For primary outcome proportion of therapy failures and their 95 CI will be calculated for both the two regimens Then the researchers will compare proportion of therapy failure using alternative criteria and WHO defined conventional therapy failure criteria
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