RCTs in child health in developing countries 2007-2008
RANDOMISED TRIALS IN CHILD
HEALTH IN DEVELOPING
COUNTRIES
6th Edition
July 2007-June 2008
www.ichrc.org
Please send suggestions about this booklet to:
A-Prof Trevor Duke
Centre for International Child Health
University Department of Paediatrics
Royal Children’s Hospital
Parkville, 3052, Victoria, Australia
Telephone: (613) 9345 5968 / 9345 5522
Fax: (613) 9345 6667
Email: trevor.duke@rch.org.au
Randomised trials in child health in developing countries 2007-08
SEARCH STRATEGY
Pubmed Hayne’s strategy, search: ((Developing countries; Developing country; Countries,
developing; Developed countries; Country, developing; Countries, developed; Developed
country; Country, developed; Nations, developing; Developing nations OR India OR Africa OR
Asia OR South America OR Papua New Guinea OR Asia-Pacific) and (Child*)) AND
(randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND
controlled[Title/Abstract] AND trial[Title/Abstract])).
Introduction .................................................................................................................................. 3
Acute respiratory infection........................................................................................................... 5
Anaemia ..................................................................................................................................... 10
Anaesthesia and intensive care................................................................................................... 10
Asthma ....................................................................................................................................... 15
Dengue ....................................................................................................................................... 19
Diarrhoea.................................................................................................................................... 20
Epilepsy...................................................................................................................................... 24
Fever........................................................................................................................................... 26
Filariasis ..................................................................................................................................... 28
Gastrointestinal parasitic infections ........................................................................................... 28
HIV / AIDS ................................................................................................................................ 30
Case management and anti-retroviral therapy....................................................................... 30
HIV education ....................................................................................................................... 32
Prevention of parent to child transmission ............................................................................ 33
Injury prevention........................................................................................................................ 37
Leishmaniasis............................................................................................................................. 38
Leprosy....................................................................................................................................... 39
Malaria ....................................................................................................................................... 39
Malaria vaccine ..................................................................................................................... 39
Intermittent preventative treatment ....................................................................................... 42
Rapid diagnostic tests ............................................................................................................ 48
Insecticide treated materials .................................................................................................. 48
Treatment of uncomplicated malaria..................................................................................... 50
Treatment of severe or complicated malaria ......................................................................... 65
Malnutrition................................................................................................................................ 68
Maternal care and maternal nutrition ......................................................................................... 69
Measles....................................................................................................................................... 74
Neonatal care.............................................................................................................................. 75
Neurology................................................................................................................................... 81
Neurocysticercosis ..................................................................................................................... 82
Nutrition, micronutrients and breast feeding ............................................................................. 83
Oral health.................................................................................................................................. 91
Ophthalmology........................................................................................................................... 92
Quality of care............................................................................................................................ 93
School health.............................................................................................................................. 94
Skin disease................................................................................................................................ 96
Surgical problems....................................................................................................................... 98
Supportive care......................................................................................................................... 100
Tuberculosis ............................................................................................................................. 102
Vaccines ................................................................................................................................... 103
Vitamin A................................................................................................................................. 110
Zinc .......................................................................................................................................... 115
2
Randomised trials in child health in developing countries 2007-08
Introduction
This booklet is compiled annually to summarize the evidence on child health derived from
randomized trials in developing countries over the previous year. The aim is to make this
information widely available to paediatricians, nurses, other health workers and administrators
in resource poor settings where up-to-date information is hard to find. It is hoped that such
information will be helpful in reviewing treatment policies, clinical practice and public health
strategies.
The method of searching for studies to include uses Pubmed, a search engine that is freely
available and widely used in most countries throughout the world. The search strategy has been
chosen to try to capture as many relevant studies as possible, although it is possible that some
are missed. If you know of a relevant RCT that has not been included in this year’s review,
please let me know. The search strategy is reproducible by anyone with access to the Internet,
through http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
Randomized controlled trials (RCTs) are far from the only valuable scientific evidence, and
some RCTs, because of problems with design or implementation have limited value. However
the method of the Randomized Trial is the Gold Standard for determining attributable benefit or
harm from clinical and public health interventions. When appropriately performed they
eliminate bias and confounding. However their results should not be accepted uncritically and
they should be evaluated for quality and validity. Before the result of an RCT can be
generalized to another setting there must be consideration of the wider applicability, feasibility
and potential for sustainability.
This year there were 161 studies identified. These came from all regions of the world, mostly
from developing country researchers. Several trials from 2007-08 may lead to significant
changes in child health approaches or clinical recommendations. Some key findings include:
•
Outpatient treatment of WHO defined severe pneumonia was shown to be safe and
effective in children without complications and in areas that are not HIV endemic
•
Giving zinc and ORS to children with diarrhoea improves prescribing of ORS, and
reduces subsequent morbidity from acute respiratory infection
•
In HIV-affected infants in Zambia, mortality was higher when there was abrupt weaning
from breast milk at 4 months of age.
•
Giving mothers nevirapine or nevirapine and zidovudine for 14 weeks has a strong
protective effect against HIV transmission through breast milk.
•
A package of home-based antenatal and neonatal care reduced neonatal mortality in
Bangladesh
•
In Kenya there has been sustained benefit on child survival of insecticide treated bednets; it was estimated that 7 deaths were averted for every 1000 bed-nets distributed.
•
Topically applied sunflower oil improved survival rates among preterm hospitalized
infants in Bangladesh.
•
Rectally administered quinine is effective for the treatment of severe malaria, as has
been shown with dihydroartimisinin and artesunate, useful where intravenous access is
not possible or the child is vomiting
•
IV phenytoin, IV valproate or buccal midazolam are effective and safe for the treatment
of status epilepticus. Diazepam should not be given as an IV infusion.
•
Artimisinin derivatives have important anti-schistosomal effects.
3
Randomised trials in child health in developing countries 2007-08
We have again included the web-link for papers that are freely available in full-text on the
Internet. This year there were 121 such studies, an increase on previous years indicating the
increased numbers of open access on-line journals. More importantly, through HINARI
(http://www.who.int/hinari/en/) a program set up by WHO in collaboration with major
publishers, the full-text version of over 3750 journals are available to health institutions in 113
countries. If your health institution (medical school, teaching hospital, nursing school,
government office) has not registered with HINARI, you can check your eligibility and register
online.
Please feel free to distribute this booklet to any colleagues. Previous editions (2002-2007) are
available at: www.ichrc.org
Trevor Duke
August 2008
4
Randomised trials in child health in developing countries 2007-08
Acute respiratory infection
(See also Measles)
PLoS ONE. 2008 Apr 23;3(4):e1991.
Does 3-day course of oral amoxycillin benefit children of non-severe pneumonia
with wheeze: a multicentric randomised controlled trial.
Awasthi S, Agarwal G, Kabra SK, Singhi S, Kulkarni M, More V, Niswade A, Pillai RM,
Luke R, Srivastava NM, Suresh S, Verghese VP, Raghupathy P, Lodha R, Walter SD.
King George's Medical University, Lucknow, India. sawasthi@sancharnet.in
BACKGROUND: WHO-defined pneumonias, treated with antibiotics, are responsible for a
significant proportion of childhood morbidity and mortality in the developing countries. Since
substantial proportion pneumonias have a viral etiology, where children are more likely to
present with wheeze, there is a concern that currently antibiotics are being over-prescribed for it.
Hence the current trial was conducted with the objective to show the therapeutic equivalence of
two treatments (placebo and amoxycillin) for children presenting with non-severe pneumonia
with wheeze, who have persistent fast breathing after nebulisation with salbutamol, and have
normal chest radiograph. METHODOLOGY: This multi-centric, randomised placebo controlled
double blind clinical trial intended to investigate equivalent efficacy of placebo and amoxicillin
and was conducted in ambulatory care settings in eight government hospitals in India.
Participants were children aged 2-59 months of age, who received either oral amoxycillin
(31-54 mg/Kg/day, in three divided doses for three days) or placebo, and standard
bronchodilator therapy. Primary outcome was clinical failure on or before day- 4.
PRINCIPAL FINDINGS: We randomized 836 cases in placebo and 835 in amoxycillin group.
Clinical failures occurred in 201 (24.0%) on placebo and 166 (19.9%) on amoxycillin (risk
difference 4.2% in favour of antibiotic, 95% CI: 0.2 to 8.1). Adherence for both placebo and
amoxycillin was >96% and 98.9% subjects were followed up on day- 4. Clinical failure was
associated with (i) placebo treatment (adjusted OR = 1.28, 95% CI: 1.01 to1.62), (ii) excess
respiratory rate of >10 breaths per minute (adjusted OR = 1.51, 95% CI: 1.19, 1.92), (iii)
vomiting at enrolment (adjusted OR = 1.49, 95% CI: 1.13, 1.96), (iv) history of use of bronchodilators (adjusted OR = 1.71, 95% CI: 1.30, 2.24) and (v) non-adherence (adjusted OR = 8.06,
95% CI: 4.36, 14.92). CONCLUSIONS: Treating children with non-severe pneumonia and
wheeze with a placebo is not equivalent to treatment with oral amoxycillin. TRIAL
REGISTRATION: ClinicalTrials.gov NCT00407394.
BMJ. 2008 Jan 12;336(7635):80-4. Epub 2008 Jan 8.
5
Randomised trials in child health in developing countries 2007-08
Chloramphenicol versus ampicillin plus gentamicin for community acquired
very severe pneumonia among children aged 2-59 months in low resource
settings: multicentre randomised controlled trial (SPEAR study).
Asghar R, Banajeh S, Egas J, Hibberd P, Iqbal I, Katep-Bwalya M, Kundi Z, Law P,
MacLeod W, Maulen-Radovan I, Mino G, Saha S, Sempertegui F, Simon J, Santosham M,
Singhi S, Thea DM, Qazi S; Severe Pneumonia Evaluation Antimicrobial Research Study
Group.
Rawalpindi General Hospital, Rawalpindi, Pakistan.
OBJECTIVE: To evaluate whether five days' treatment with injectable ampicillin plus
gentamicin compared with chloramphenicol reduces treatment failure in children aged 2-59
months with community acquired very severe pneumonia in low resource settings. DESIGN:
Open label randomised controlled trial. SETTING: Inpatient wards within tertiary care hospitals
in Bangladesh, Ecuador, India, Mexico, Pakistan, Yemen, and Zambia. PARTICIPANTS:
Children aged 2-59 months with WHO defined very severe pneumonia. INTERVENTION:
Chloramphenicol versus a combination of ampicillin plus gentamicin. MAIN OUTCOME
MEASURES: Primary outcome measure was treatment failure at five days. Secondary outcomes
were treatment failure defined similarly among all participants evaluated at 48 hours and at 10
and 21 days. RESULTS: More children failed treatment with chloramphenicol at day 5
(16% v 11%; relative risk 1.43, 95% confidence interval 1.03 to 1.97) and also by days 10
and 21. Overall, 112 bacterial isolates were obtained from blood and lung aspirates in 110
children (11.5%), with the most common organisms being Staphylococcus aureus (n=47) and
Streptococcus pneumoniae (n=22). In subgroup analysis, bacteraemia with any organism
increased the risk of treatment failure at 21 days in the chloramphenicol group (2.09, 1.41 to
3.10) but not in the ampicillin plus gentamicin group (1.12, 0.59 to 2.13). Similarly, isolation of
S pneumoniae increased the risk of treatment failure at day 21 (4.06, 2.73 to 6.03) and death
(5.80, 2.62 to 12.85) in the chloramphenicol group but not in the ampicillin plus gentamicin
group. No difference was found in treatment failure for children with S aureus bacteraemia in
the two groups, but the power to detect a difference in this subgroup analysis was low.
Independent predictors of treatment failure by multivariate analysis were hypoxaemia (oxygen
saturation
HEALTH IN DEVELOPING
COUNTRIES
6th Edition
July 2007-June 2008
www.ichrc.org
Please send suggestions about this booklet to:
A-Prof Trevor Duke
Centre for International Child Health
University Department of Paediatrics
Royal Children’s Hospital
Parkville, 3052, Victoria, Australia
Telephone: (613) 9345 5968 / 9345 5522
Fax: (613) 9345 6667
Email: trevor.duke@rch.org.au
Randomised trials in child health in developing countries 2007-08
SEARCH STRATEGY
Pubmed Hayne’s strategy, search: ((Developing countries; Developing country; Countries,
developing; Developed countries; Country, developing; Countries, developed; Developed
country; Country, developed; Nations, developing; Developing nations OR India OR Africa OR
Asia OR South America OR Papua New Guinea OR Asia-Pacific) and (Child*)) AND
(randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND
controlled[Title/Abstract] AND trial[Title/Abstract])).
Introduction .................................................................................................................................. 3
Acute respiratory infection........................................................................................................... 5
Anaemia ..................................................................................................................................... 10
Anaesthesia and intensive care................................................................................................... 10
Asthma ....................................................................................................................................... 15
Dengue ....................................................................................................................................... 19
Diarrhoea.................................................................................................................................... 20
Epilepsy...................................................................................................................................... 24
Fever........................................................................................................................................... 26
Filariasis ..................................................................................................................................... 28
Gastrointestinal parasitic infections ........................................................................................... 28
HIV / AIDS ................................................................................................................................ 30
Case management and anti-retroviral therapy....................................................................... 30
HIV education ....................................................................................................................... 32
Prevention of parent to child transmission ............................................................................ 33
Injury prevention........................................................................................................................ 37
Leishmaniasis............................................................................................................................. 38
Leprosy....................................................................................................................................... 39
Malaria ....................................................................................................................................... 39
Malaria vaccine ..................................................................................................................... 39
Intermittent preventative treatment ....................................................................................... 42
Rapid diagnostic tests ............................................................................................................ 48
Insecticide treated materials .................................................................................................. 48
Treatment of uncomplicated malaria..................................................................................... 50
Treatment of severe or complicated malaria ......................................................................... 65
Malnutrition................................................................................................................................ 68
Maternal care and maternal nutrition ......................................................................................... 69
Measles....................................................................................................................................... 74
Neonatal care.............................................................................................................................. 75
Neurology................................................................................................................................... 81
Neurocysticercosis ..................................................................................................................... 82
Nutrition, micronutrients and breast feeding ............................................................................. 83
Oral health.................................................................................................................................. 91
Ophthalmology........................................................................................................................... 92
Quality of care............................................................................................................................ 93
School health.............................................................................................................................. 94
Skin disease................................................................................................................................ 96
Surgical problems....................................................................................................................... 98
Supportive care......................................................................................................................... 100
Tuberculosis ............................................................................................................................. 102
Vaccines ................................................................................................................................... 103
Vitamin A................................................................................................................................. 110
Zinc .......................................................................................................................................... 115
2
Randomised trials in child health in developing countries 2007-08
Introduction
This booklet is compiled annually to summarize the evidence on child health derived from
randomized trials in developing countries over the previous year. The aim is to make this
information widely available to paediatricians, nurses, other health workers and administrators
in resource poor settings where up-to-date information is hard to find. It is hoped that such
information will be helpful in reviewing treatment policies, clinical practice and public health
strategies.
The method of searching for studies to include uses Pubmed, a search engine that is freely
available and widely used in most countries throughout the world. The search strategy has been
chosen to try to capture as many relevant studies as possible, although it is possible that some
are missed. If you know of a relevant RCT that has not been included in this year’s review,
please let me know. The search strategy is reproducible by anyone with access to the Internet,
through http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
Randomized controlled trials (RCTs) are far from the only valuable scientific evidence, and
some RCTs, because of problems with design or implementation have limited value. However
the method of the Randomized Trial is the Gold Standard for determining attributable benefit or
harm from clinical and public health interventions. When appropriately performed they
eliminate bias and confounding. However their results should not be accepted uncritically and
they should be evaluated for quality and validity. Before the result of an RCT can be
generalized to another setting there must be consideration of the wider applicability, feasibility
and potential for sustainability.
This year there were 161 studies identified. These came from all regions of the world, mostly
from developing country researchers. Several trials from 2007-08 may lead to significant
changes in child health approaches or clinical recommendations. Some key findings include:
•
Outpatient treatment of WHO defined severe pneumonia was shown to be safe and
effective in children without complications and in areas that are not HIV endemic
•
Giving zinc and ORS to children with diarrhoea improves prescribing of ORS, and
reduces subsequent morbidity from acute respiratory infection
•
In HIV-affected infants in Zambia, mortality was higher when there was abrupt weaning
from breast milk at 4 months of age.
•
Giving mothers nevirapine or nevirapine and zidovudine for 14 weeks has a strong
protective effect against HIV transmission through breast milk.
•
A package of home-based antenatal and neonatal care reduced neonatal mortality in
Bangladesh
•
In Kenya there has been sustained benefit on child survival of insecticide treated bednets; it was estimated that 7 deaths were averted for every 1000 bed-nets distributed.
•
Topically applied sunflower oil improved survival rates among preterm hospitalized
infants in Bangladesh.
•
Rectally administered quinine is effective for the treatment of severe malaria, as has
been shown with dihydroartimisinin and artesunate, useful where intravenous access is
not possible or the child is vomiting
•
IV phenytoin, IV valproate or buccal midazolam are effective and safe for the treatment
of status epilepticus. Diazepam should not be given as an IV infusion.
•
Artimisinin derivatives have important anti-schistosomal effects.
3
Randomised trials in child health in developing countries 2007-08
We have again included the web-link for papers that are freely available in full-text on the
Internet. This year there were 121 such studies, an increase on previous years indicating the
increased numbers of open access on-line journals. More importantly, through HINARI
(http://www.who.int/hinari/en/) a program set up by WHO in collaboration with major
publishers, the full-text version of over 3750 journals are available to health institutions in 113
countries. If your health institution (medical school, teaching hospital, nursing school,
government office) has not registered with HINARI, you can check your eligibility and register
online.
Please feel free to distribute this booklet to any colleagues. Previous editions (2002-2007) are
available at: www.ichrc.org
Trevor Duke
August 2008
4
Randomised trials in child health in developing countries 2007-08
Acute respiratory infection
(See also Measles)
PLoS ONE. 2008 Apr 23;3(4):e1991.
Does 3-day course of oral amoxycillin benefit children of non-severe pneumonia
with wheeze: a multicentric randomised controlled trial.
Awasthi S, Agarwal G, Kabra SK, Singhi S, Kulkarni M, More V, Niswade A, Pillai RM,
Luke R, Srivastava NM, Suresh S, Verghese VP, Raghupathy P, Lodha R, Walter SD.
King George's Medical University, Lucknow, India. sawasthi@sancharnet.in
BACKGROUND: WHO-defined pneumonias, treated with antibiotics, are responsible for a
significant proportion of childhood morbidity and mortality in the developing countries. Since
substantial proportion pneumonias have a viral etiology, where children are more likely to
present with wheeze, there is a concern that currently antibiotics are being over-prescribed for it.
Hence the current trial was conducted with the objective to show the therapeutic equivalence of
two treatments (placebo and amoxycillin) for children presenting with non-severe pneumonia
with wheeze, who have persistent fast breathing after nebulisation with salbutamol, and have
normal chest radiograph. METHODOLOGY: This multi-centric, randomised placebo controlled
double blind clinical trial intended to investigate equivalent efficacy of placebo and amoxicillin
and was conducted in ambulatory care settings in eight government hospitals in India.
Participants were children aged 2-59 months of age, who received either oral amoxycillin
(31-54 mg/Kg/day, in three divided doses for three days) or placebo, and standard
bronchodilator therapy. Primary outcome was clinical failure on or before day- 4.
PRINCIPAL FINDINGS: We randomized 836 cases in placebo and 835 in amoxycillin group.
Clinical failures occurred in 201 (24.0%) on placebo and 166 (19.9%) on amoxycillin (risk
difference 4.2% in favour of antibiotic, 95% CI: 0.2 to 8.1). Adherence for both placebo and
amoxycillin was >96% and 98.9% subjects were followed up on day- 4. Clinical failure was
associated with (i) placebo treatment (adjusted OR = 1.28, 95% CI: 1.01 to1.62), (ii) excess
respiratory rate of >10 breaths per minute (adjusted OR = 1.51, 95% CI: 1.19, 1.92), (iii)
vomiting at enrolment (adjusted OR = 1.49, 95% CI: 1.13, 1.96), (iv) history of use of bronchodilators (adjusted OR = 1.71, 95% CI: 1.30, 2.24) and (v) non-adherence (adjusted OR = 8.06,
95% CI: 4.36, 14.92). CONCLUSIONS: Treating children with non-severe pneumonia and
wheeze with a placebo is not equivalent to treatment with oral amoxycillin. TRIAL
REGISTRATION: ClinicalTrials.gov NCT00407394.
BMJ. 2008 Jan 12;336(7635):80-4. Epub 2008 Jan 8.
5
Randomised trials in child health in developing countries 2007-08
Chloramphenicol versus ampicillin plus gentamicin for community acquired
very severe pneumonia among children aged 2-59 months in low resource
settings: multicentre randomised controlled trial (SPEAR study).
Asghar R, Banajeh S, Egas J, Hibberd P, Iqbal I, Katep-Bwalya M, Kundi Z, Law P,
MacLeod W, Maulen-Radovan I, Mino G, Saha S, Sempertegui F, Simon J, Santosham M,
Singhi S, Thea DM, Qazi S; Severe Pneumonia Evaluation Antimicrobial Research Study
Group.
Rawalpindi General Hospital, Rawalpindi, Pakistan.
OBJECTIVE: To evaluate whether five days' treatment with injectable ampicillin plus
gentamicin compared with chloramphenicol reduces treatment failure in children aged 2-59
months with community acquired very severe pneumonia in low resource settings. DESIGN:
Open label randomised controlled trial. SETTING: Inpatient wards within tertiary care hospitals
in Bangladesh, Ecuador, India, Mexico, Pakistan, Yemen, and Zambia. PARTICIPANTS:
Children aged 2-59 months with WHO defined very severe pneumonia. INTERVENTION:
Chloramphenicol versus a combination of ampicillin plus gentamicin. MAIN OUTCOME
MEASURES: Primary outcome measure was treatment failure at five days. Secondary outcomes
were treatment failure defined similarly among all participants evaluated at 48 hours and at 10
and 21 days. RESULTS: More children failed treatment with chloramphenicol at day 5
(16% v 11%; relative risk 1.43, 95% confidence interval 1.03 to 1.97) and also by days 10
and 21. Overall, 112 bacterial isolates were obtained from blood and lung aspirates in 110
children (11.5%), with the most common organisms being Staphylococcus aureus (n=47) and
Streptococcus pneumoniae (n=22). In subgroup analysis, bacteraemia with any organism
increased the risk of treatment failure at 21 days in the chloramphenicol group (2.09, 1.41 to
3.10) but not in the ampicillin plus gentamicin group (1.12, 0.59 to 2.13). Similarly, isolation of
S pneumoniae increased the risk of treatment failure at day 21 (4.06, 2.73 to 6.03) and death
(5.80, 2.62 to 12.85) in the chloramphenicol group but not in the ampicillin plus gentamicin
group. No difference was found in treatment failure for children with S aureus bacteraemia in
the two groups, but the power to detect a difference in this subgroup analysis was low.
Independent predictors of treatment failure by multivariate analysis were hypoxaemia (oxygen
saturation