Ignite Creation Date:
2024-05-05 @ 11:47 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00131716
Status:
COMPLETED
Last Update Posted:
2017-01-12
First Post:
2005-08-18
Brief Title:
Prevention of Severe Anaemia in Gambian Children
Sponsor:
London School of Hygiene and Tropical Medicine
Organization:
London School of Hygiene and Tropical Medicine
Study Overview
Official Title:
Chemoprophylaxis With Sulfadoxine-pyrimethamine to Prevent Recurrence of Severe Anaemia in Gambian Children Aged 3 Months to 9 Years
Status:
COMPLETED
Status Verified Date:
2017-01
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:
Severe anaemia is a frequent cause of admission to hospitals in tropical Africa and about 10 of such children die In endemic countries anaemia has multiple causes such as nutritional deficiencies infections and haemoglobinopathies However Plasmodium falciparum infection is believed to be the major contributory factor to the aetiology of severe anaemia Severe anaemia is usually treated by blood transfusion although transfusion carries the attendant risk of transmission of HIV and other blood-borne infections Thus there is a need to explore novel strategies to reduce the incidence of severe anaemia in high-risk groups such as children with suboptimal haemoglobin levels because these children are at increased risk of developing severe anaemia if they develop a malaria infection before their haemoglobin level has normalized Therefore it is proposed to study whether monthly chemoprophylaxis with sulphadoxinepyrimethamine SP given during malaria transmission season can protect Gambian children from developing severe anaemia After receiving treatment from the hospital 1200 children admitted to the hospital with a haematocrit of less than 21 were randomised to receive either monthly SP or placebo during the rest of the malaria transmission season Morbidity was monitored throughout the rainy season Study subjects were seen at the end of the dry season to document morbidity and mortality
Detailed Description:
Objectives
1 To assess the effectiveness of monthly prophylaxis with SP on haematological recovery in children who have been treated for severe anaemia
2 To measure compliance with the intervention
3 To investigate whether or not infection with chloroquine and SP resistant strains contributes to the pathogenesis of severe anaemia
Study design and methods
Study site
The study was based at the 75-bed paediatric unit of The Royal Victoria Hospital RVH which is located in the capital Banjul This is the main referral hospital for the country The paediatric unit admits about 7000 children a year of whom about 800 are anaemic PCV 33
Enrolment of children
Study subjects were recruited fom paediatric unit of RVH MRC Hospital and Brikama Essau and Sibanor Health Centres Study subjects were enrolled by non-coercive methods if they fulfil the inclusion criteria and had none of the exclusion criteria
Screening process and enrolment
Patients were recruited on presentation to the ward All children in the right age group who presented to the ward had their haematocrit and blood film done by a project field worker Children with a PCV of less than 21 were offered assessment by a project doctor If assessment was permitted and the patient fulfilled the entry criteria then written consent was sought from the parentguardian The study was explained in the parents guardians preferred language and written informed consent was obtained on approved forms
On entry into the trial a detailed clinical history drug history family history and information on bednet usage and impregnation was obtained The study physician examined the child documented nutritional status and recorded the findings in a case report form In addition a detailed address was obtained Each study child was provided with a photo ID card to facilitate identification at each contact
A 5-ml baseline blood sample was obtained for determination of the following
Hb red cell indices white cell and platelet count Coulter counter
Reticulocyte count
Markers of iron status serum iron and ferritin first 100 children
Sickling test and if positive haemoglobin electrophoresis
Stool examination for hookworm and other parasites first 100 children
Other investigations such as chest x-ray and urine examinations were carried out as clinically indicated
Inpatient management
During admission children with malaria were treated with IM quinine or chloroquine plus SP as clinically indicated Children with a PCV 15 and those with signs of respiratory distress andor a gallop rhythm were transfused In addition all patients received iron for 28 days treatment starting at the time of their discharge from hospital Patients were treated for other conditions as clinically indicated
Treatment regimens
Treatment was given as follows
SP tablets containing 500 mg sulfadoxine 25 mg pyrimethamine at an approximate dose of 125 mg pyrimethamine25 mg sulphadoxine per kg stat dose
Oral chloroquine 10mg daily for 3 days
Sc chloroquine 5mgkg 6 hourly x 7 doses
IM Quinine 20 mgkg loading dose then 10 mgkg 12 hourly for 5 days
Iron was given as syrup at a target dose of 2 mgkg elemental iron
Assessment of resistance to chloroquine and antifolates
To investigate whether or not infection with chloroquine or SP resistant parasites contributes to the pathogenesis of severe anaemia in Gambian children filter paper blood samples were collected from the first 100 children entered into the study who have Pfalciparum parasitaemia and an equal number of aged matched children who attended the OPD clinic with uncomplicated symptomatic malaria Nested PCR on extracted DNA was used to tested for mutation in genes associated with resistance Pfcrt and Pfmdr for chloroquine and DHRF DHPS genes for SP using standard techniques
Study subjects were individually randomised into either the SP or the placebo group in a 11 fashion at the time of discharge from hospital although chemoprophylaxis was not be started for another week as the children are likely to have received antimalarials whilst in hospital Randomisation was in blocks Block size were selected to enhance blinding and maintain balance in the treatment allocation ratio as recruitment progresses
Home visit
As soon as possible after discharge from hospital patients were visited at home by a project field worker to collect information on social economic and environmental risk factors that may predisposes an individual child to develop severe anaemia A housing survey was conducted during this visit to determine possible risk factors for malaria which might act as confounders in determination of the primary trial end-point Field workers interviewed the parentsguardians of study subject to record characteristics about the house that might influence mosquito biting behaviour These items included building material an evaluation of the presence of eaves impregnation and condition of bed nets During the visit parents were encouraged to protect the study child with a bed net
First OPD visit after discharge from hospital One week after discharge study subjects enrolled in the study were asked to return to the OPD clinic for routine assessment At this visit a fingerprick blood sample was collected for PCV measurement and thick blood film for malaria parasite The first dose of trial medication was given during this visit
Randomisation
SP and matching placebo identical shape and size were stored in 8 boxes labelled 1 to 8 4 for SP tablets and 4 for placebo The randomisation code were kept in sealed opaque envelopes by the local safety monitor who alone will knew the code which associated each treatment group with either SP or placebo
Continuation of chemoprophylaxis in the health centre
Study subjects received their monthly chemoprophylaxis at their local health centre under direct supervision by staff of the health centre identified by the health centre and trained to take this important role in the study Health centre staff were provided with a list containing the study number photographs and randomisation group of each study subject Study subjects were observed for 30 minutes after dosing and if vomiting occurs within 30 minutes the dose was repeated SP tablets containing 500 mg sulfadoxine 25 mg pyrimethamine will be given at an approximate dose of 125 mg pyrimethamine25 mg sulphadoxine per kg Enrolment of patients started in July and surveillance continued until end of malaria transmission season
Morbidity surveillance during the rainy season
Study subjects were followed throughout the rainy season Mothersguardians were encouraged to take their child to the RVH OPD clinic or the health centre identified as being closest to their home at any time after discharge if the child became unwell Project staff were based at each of these health centres initially to identify children in the trial and to ensure that they were seen properly investigated and treated promptly by health centre staff At each visit axillary temperature was recorded using a digital thermometer A dipstick for diagnosis of malaria was used to guide treatment if fever axillary temperature of 375C or history of fever within the previous 48 hours is present In addition a thick blood smear for malaria parasites was collected for subsequent confirmation of the diagnosis Filter paper sample to test for SP resistance were collected from all malaria cases detected during morbidity surveillance Study subjects with documented fever axillary temperature of 375C or history of recent fever and malaria parasitaemia were treated with SP and chloroquine The treatment of study subjects seen at the health centres was the carried out by health centre staff in accordance with national guidelines Study patients who needed admission were referred to RVH paediatric unit or the MRC ward
End of malaria transmission season cross-sectional survey
Children enrolled in the study were seen at the OPD clinic at the end of malaria transmission season for examination by a study physician and a finger-prick blood sample was obtained for preparation of thick blood smear and determination of haematocrit A standardized questionnaire was administered to the parentsguardians of the study subject to collect information regarding illness that had occurred since the last visit symptoms experienced use of healthcare facilities and use of medicines Information on the use of bednets was collected again at this visit
Dry season follow-up
At the end of the dry season study subjects visited once During this visit a questionnaire was administered to document morbidity and mortality
Sample size calculations
Assuming an attack rate of 01 episodes of clinical malaria as defined for the primary end-point per month in children in the control group a figure based on previous surveys from The Gambia and a drop out rate during follow up of 15 131 episodes was expected in children in the control group followed until the end of one malaria transmission season Thus with a total of 1200 children recruited to the trial the study will have an 80 power to detect at 5 level of significance a 32 reduction in incidence of clinical attacks of malaria in children who receive chemoprophylaxis
Previous studies in The Gambia indicate that about 20 of children under 5 years of age have a PCV of 20 at the end of the malaria transmission season With 1200 children enrolled this trial will have a 80 power to detect a 34 reduction in the prevalence of anaemia of this degree of severity
1 To assess the effectiveness of monthly prophylaxis with SP on haematological recovery in children who have been treated for severe anaemia
2 To measure compliance with the intervention
3 To investigate whether or not infection with chloroquine and SP resistant strains contributes to the pathogenesis of severe anaemia
Study design and methods
Study site
The study was based at the 75-bed paediatric unit of The Royal Victoria Hospital RVH which is located in the capital Banjul This is the main referral hospital for the country The paediatric unit admits about 7000 children a year of whom about 800 are anaemic PCV 33
Enrolment of children
Study subjects were recruited fom paediatric unit of RVH MRC Hospital and Brikama Essau and Sibanor Health Centres Study subjects were enrolled by non-coercive methods if they fulfil the inclusion criteria and had none of the exclusion criteria
Screening process and enrolment
Patients were recruited on presentation to the ward All children in the right age group who presented to the ward had their haematocrit and blood film done by a project field worker Children with a PCV of less than 21 were offered assessment by a project doctor If assessment was permitted and the patient fulfilled the entry criteria then written consent was sought from the parentguardian The study was explained in the parents guardians preferred language and written informed consent was obtained on approved forms
On entry into the trial a detailed clinical history drug history family history and information on bednet usage and impregnation was obtained The study physician examined the child documented nutritional status and recorded the findings in a case report form In addition a detailed address was obtained Each study child was provided with a photo ID card to facilitate identification at each contact
A 5-ml baseline blood sample was obtained for determination of the following
Hb red cell indices white cell and platelet count Coulter counter
Reticulocyte count
Markers of iron status serum iron and ferritin first 100 children
Sickling test and if positive haemoglobin electrophoresis
Stool examination for hookworm and other parasites first 100 children
Other investigations such as chest x-ray and urine examinations were carried out as clinically indicated
Inpatient management
During admission children with malaria were treated with IM quinine or chloroquine plus SP as clinically indicated Children with a PCV 15 and those with signs of respiratory distress andor a gallop rhythm were transfused In addition all patients received iron for 28 days treatment starting at the time of their discharge from hospital Patients were treated for other conditions as clinically indicated
Treatment regimens
Treatment was given as follows
SP tablets containing 500 mg sulfadoxine 25 mg pyrimethamine at an approximate dose of 125 mg pyrimethamine25 mg sulphadoxine per kg stat dose
Oral chloroquine 10mg daily for 3 days
Sc chloroquine 5mgkg 6 hourly x 7 doses
IM Quinine 20 mgkg loading dose then 10 mgkg 12 hourly for 5 days
Iron was given as syrup at a target dose of 2 mgkg elemental iron
Assessment of resistance to chloroquine and antifolates
To investigate whether or not infection with chloroquine or SP resistant parasites contributes to the pathogenesis of severe anaemia in Gambian children filter paper blood samples were collected from the first 100 children entered into the study who have Pfalciparum parasitaemia and an equal number of aged matched children who attended the OPD clinic with uncomplicated symptomatic malaria Nested PCR on extracted DNA was used to tested for mutation in genes associated with resistance Pfcrt and Pfmdr for chloroquine and DHRF DHPS genes for SP using standard techniques
Study subjects were individually randomised into either the SP or the placebo group in a 11 fashion at the time of discharge from hospital although chemoprophylaxis was not be started for another week as the children are likely to have received antimalarials whilst in hospital Randomisation was in blocks Block size were selected to enhance blinding and maintain balance in the treatment allocation ratio as recruitment progresses
Home visit
As soon as possible after discharge from hospital patients were visited at home by a project field worker to collect information on social economic and environmental risk factors that may predisposes an individual child to develop severe anaemia A housing survey was conducted during this visit to determine possible risk factors for malaria which might act as confounders in determination of the primary trial end-point Field workers interviewed the parentsguardians of study subject to record characteristics about the house that might influence mosquito biting behaviour These items included building material an evaluation of the presence of eaves impregnation and condition of bed nets During the visit parents were encouraged to protect the study child with a bed net
First OPD visit after discharge from hospital One week after discharge study subjects enrolled in the study were asked to return to the OPD clinic for routine assessment At this visit a fingerprick blood sample was collected for PCV measurement and thick blood film for malaria parasite The first dose of trial medication was given during this visit
Randomisation
SP and matching placebo identical shape and size were stored in 8 boxes labelled 1 to 8 4 for SP tablets and 4 for placebo The randomisation code were kept in sealed opaque envelopes by the local safety monitor who alone will knew the code which associated each treatment group with either SP or placebo
Continuation of chemoprophylaxis in the health centre
Study subjects received their monthly chemoprophylaxis at their local health centre under direct supervision by staff of the health centre identified by the health centre and trained to take this important role in the study Health centre staff were provided with a list containing the study number photographs and randomisation group of each study subject Study subjects were observed for 30 minutes after dosing and if vomiting occurs within 30 minutes the dose was repeated SP tablets containing 500 mg sulfadoxine 25 mg pyrimethamine will be given at an approximate dose of 125 mg pyrimethamine25 mg sulphadoxine per kg Enrolment of patients started in July and surveillance continued until end of malaria transmission season
Morbidity surveillance during the rainy season
Study subjects were followed throughout the rainy season Mothersguardians were encouraged to take their child to the RVH OPD clinic or the health centre identified as being closest to their home at any time after discharge if the child became unwell Project staff were based at each of these health centres initially to identify children in the trial and to ensure that they were seen properly investigated and treated promptly by health centre staff At each visit axillary temperature was recorded using a digital thermometer A dipstick for diagnosis of malaria was used to guide treatment if fever axillary temperature of 375C or history of fever within the previous 48 hours is present In addition a thick blood smear for malaria parasites was collected for subsequent confirmation of the diagnosis Filter paper sample to test for SP resistance were collected from all malaria cases detected during morbidity surveillance Study subjects with documented fever axillary temperature of 375C or history of recent fever and malaria parasitaemia were treated with SP and chloroquine The treatment of study subjects seen at the health centres was the carried out by health centre staff in accordance with national guidelines Study patients who needed admission were referred to RVH paediatric unit or the MRC ward
End of malaria transmission season cross-sectional survey
Children enrolled in the study were seen at the OPD clinic at the end of malaria transmission season for examination by a study physician and a finger-prick blood sample was obtained for preparation of thick blood smear and determination of haematocrit A standardized questionnaire was administered to the parentsguardians of the study subject to collect information regarding illness that had occurred since the last visit symptoms experienced use of healthcare facilities and use of medicines Information on the use of bednets was collected again at this visit
Dry season follow-up
At the end of the dry season study subjects visited once During this visit a questionnaire was administered to document morbidity and mortality
Sample size calculations
Assuming an attack rate of 01 episodes of clinical malaria as defined for the primary end-point per month in children in the control group a figure based on previous surveys from The Gambia and a drop out rate during follow up of 15 131 episodes was expected in children in the control group followed until the end of one malaria transmission season Thus with a total of 1200 children recruited to the trial the study will have an 80 power to detect at 5 level of significance a 32 reduction in incidence of clinical attacks of malaria in children who receive chemoprophylaxis
Previous studies in The Gambia indicate that about 20 of children under 5 years of age have a PCV of 20 at the end of the malaria transmission season With 1200 children enrolled this trial will have a 80 power to detect a 34 reduction in the prevalence of anaemia of this degree of severity
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