Ignite Creation Date:
2024-05-05 @ 11:49 AM
Last Modification Date:
2024-10-26 @ 9:14 AM
Study NCT ID:
NCT00140517
Status:
COMPLETED
Last Update Posted:
2017-01-12
First Post:
2005-08-31
Brief Title:
Relationships Between the Use of Antimalarial Drugs in Pregnancy and Plasmodium Falciparum Resistance
Sponsor:
London School of Hygiene and Tropical Medicine
Organization:
London School of Hygiene and Tropical Medicine
Study Overview
Official Title:
Relationships Between the Use of Antimalarial Drugs in Pregnancy and Plasmodium Falciparum Resistance
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:
Plasmodium falciparum resistance to chloroquine CQ and sulfadoxine-pyrimethamine SP continue to spread impeding control of this important disease CQ and SP are still the most commonly used antimalarial drugs for malaria prevention during pregnancy and might be made less effective by resistance However the treatment and prophylaxis regimens used may also create conditions for selecting resistant malaria parasite strains A better understanding of the relationships between chemoprophylaxis regimens and resistance would be helpful to improve chemoprophylaxis of malaria in pregnancy
This work aims to improve the use of chemoprophylaxis in pregnancy by determining whether there is a relationship between the use of standard prophylactic regimens with CQ and SP and the occurrence of P falciparum resistant strains in pregnant women The study consists of 2 parts The first part is a randomized trial comparing 3 chemoprophylactic treatment groups - weekly CQ after initial presumptive CQ treatment - CQ intermittent presumptive treatment given as a standard dose at 2nd and 3rd trimester respectively and SP intermittent presumptive treatment given as a single dose at 2nd and 3rd trimester respectively These treatment groups will also be compared to a group of women delivering at the same health centre but who have not been participating in the study The second part will be a clinical trial for assessment of clinical and parasitological efficacy of CQ and SP treatment in pregnant women presenting with uncomplicated malaria attacks
The study will be conducted from October 2002 to March 2005 in a health centre of Ouagadougou Burkina Faso where malaria transmission is seasonal and resistance to CQ and SP is low
This work aims to improve the use of chemoprophylaxis in pregnancy by determining whether there is a relationship between the use of standard prophylactic regimens with CQ and SP and the occurrence of P falciparum resistant strains in pregnant women The study consists of 2 parts The first part is a randomized trial comparing 3 chemoprophylactic treatment groups - weekly CQ after initial presumptive CQ treatment - CQ intermittent presumptive treatment given as a standard dose at 2nd and 3rd trimester respectively and SP intermittent presumptive treatment given as a single dose at 2nd and 3rd trimester respectively These treatment groups will also be compared to a group of women delivering at the same health centre but who have not been participating in the study The second part will be a clinical trial for assessment of clinical and parasitological efficacy of CQ and SP treatment in pregnant women presenting with uncomplicated malaria attacks
The study will be conducted from October 2002 to March 2005 in a health centre of Ouagadougou Burkina Faso where malaria transmission is seasonal and resistance to CQ and SP is low
Detailed Description:
OBJECTIVES Overall objective To improve the use of malaria chemoprophylaxis in pregnancy
Specific objectives
To investigate the effects of weekly CQ intermittent presumptive treatment with CQ and with SP on placental peripheral and cord parasitaemia and on P falciparum resistance status in primigravidae and secundigravidae
To determine the relationships between carriage of P falciparum resistant strains and malaria morbidity attacks and anaemia during pregnancy
To determine the clinical and parasitological efficacy of CQ and SP in primigravidae and secundigravidae
MATERIAL AND METHODS
The study will be conducted in a peripheral health centre of Ouagadougou Burkina Faso West Africa
The largest part of the country is tropical savannah with a rainy season from June to October average rainfall 1000 mm per year mean temperature 25C a cold dry season from November to February min temp 15C and a hot dry season from March to May Malaria transmission is seasonal June to Decemberand the major mosquito vectors are A gambiae A funestus and A arabiensis Malaria morbidity represents 30 to 50 of febrile illnesses and is the most frequent reason for health centres attendance and hospitals admissionSince its first notification in 1986 P falciparum resistance to CQ increased slowly with a considerable variation in space and time and resistance to SP has remained low CQ clinical failures are in general less than 20 in 6-59 months children and parasitological resistance is around 30 Malaria prevention in pregnancy is given as weekly 300 mg CQ following a presumptive initial treatment as recommended by the national malaria control programme MOH ANC services in health centres provide pregnant women with CQ and haematinics The health centre Centre médical Paul VI is a peri-urban health facility of Ouagadougou It comprises general outpatient consultation service paediatric and maternity wards and a laboratoryPatients come from the peri-urban districts and the neighbouring villages
Study design
a Comparative randomized trial
Three groups will be studied Pregnant women primigravidae and secundigravidae from 12 to 24 weeks of pregnancy will be randomly assigned using random numbers lists to treatment groups A to C as defined below
Group A pregnant women receiving weekly 300 mg CQ prophylaxis after a curative dose 10mgkg at days 1 and 2 5mgkg at day 3 at the first visit
Group B pregnant women receiving a presumptive CQ treatment at the 2nd and 3rd trimester of pregnancy 10mgkg at days 1 and 2 5mgkg at day 3
Group C pregnant women receiving a presumptive SP treatment at the 2nd and 3rd trimester of pregnancy 25mg sulfadoxine 125mg pyrimethaminekg in a single dose
Another group composed of primiparous and secundiparous women who are not part of the study and who come to deliver at the health centre group D and who have not received chloroquine prophylaxis during pregnancy will be considered as reflecting the normal situation and act as a control group These women will only be included during the first three months of the study
At inclusion
1 personal information anthropometric measures clinical data and obstetrical history will be recorded
2 fingerprick blood will be collected for a thick and a thin blood smear Hb and on filter paper for subsequent PCR tests
3 Treatment The single dose of SP and the 3 days of CQ treatment will be administered supervised by the research team
Study participants will be invited to come to the follow up visits or any time they feel sick or need health services
Follow-up visits at the beginning of second and third trimester will include
1 a clinical and parasitological examination The health events since the previous visit will be recorded Hb
2 providing chemoprophylaxis or treatment in accordance with the treatment group
At delivery the following data will be recorded
1 delivery outcomes birth weight mode of delivery APGAR score
2 mothers peripheral blood for thick blood smear Hb and filter paper for PCR
3 placental blood for thick blood smear and collection on filter paper for PCR
4 cord blood for thick blood smear If positive blood will be collected on filter paper for PCR
bClinical trial for the assessment of clinical and parasitological efficacy of CQ and SP in pregnant women
Primigravidae and secundigravidae women presenting with an uncomplicated malaria attack will be randomly treated with CQ or SP and regularly followed up to assess clinical and parasitological efficacy A molecular analysis of parasite gene mutations conferring resistance to chloroquine PfCRT and antifolates DHFR DHPS will be performed
The patients will randomly assigned to treatment with either CQ or SP They will then be followed-up during 28 days in accordance with WHO protocol The follow up criteria are clinical body temperature and parasitological peripheral parasitaemia
Sample size
a Comparative randomized trial Considering the prevalence of placenta parasitaemia to be 35 in pregnant women who do not get prophylaxis 24 in women with weekly CQ prophylaxis 15 in women with intermittent presumptive treatment with CQ and 5 in women with intermittent presumptive treatment with SP and using a significance level of 5 a power of 80 and 20 drop-out each group should include 200 subjects
a Drug efficacy assessment in pregnant women Considering the proportion of pregnant women with clinical failures to be 10-15 for chloroquine and using a significance level of 5 a power of 80 and 20 drop-out a sample of 42 subjects should be included
Methods
1 Comparative randomized trial
Pregnant women will be recruited at the ANC unit of the health facility if fulfilling the following inclusion criteria and give oral informed consent
Inclusion criteria
primi or secundigravidae - seen between 12th and 24th weeks of gestation
with a non at risk pregnancy multiple pregnancy obstetric misproportions previous caesarean high blood pressure diabetes clinical signs of AIDS
staying in a neighbouring district or village
ability to come for follow-up and delivery
Exclusion criteria
At risk pregnancy
Severe systemic disease
Wish to withdraw from participation
Inclusion and follow-up procedures
The study aims and procedures will be clearly explained to those meeting the inclusion criteriaEnrolled women will be registered and a personal health file created to be filled at enrolment follow-up and delivery Each woman will be given a health record booklet to be presented at any visit The following information will be recorded
At enrolment
Identity number date and treatment group
Name age profession place of residence address and name of husband and other close relatives
Clinical history axillary temperature body weight height clinical anaemia jaundice splenomegaly hepatomegaly stethoscopy of heart and lungs blood pressure and peripheral oedema
Obstetrical data date LMP uterine size presumed delivery date foetal heart beat previous pregnancy outcome normal abortion stillbirth complications during pregnancy and labour
Biological data Plasmodium species and density Hb filter paper blood for PCR
Follow-up
Clinical follow-up fever episodes diseases other treatments
Obstetrical follow-up uterine height foetal heart beat
Biological follow-up Plasmodium species and density Hb filter paper blood for PCR
Delivery
- Date and time labor started midwifes name
Clinical data body temperature blood pressure and clinical examination
Mode of delivery APGAR scores and birthweight
Biological data mothers peripheral parasitaemia haemoglobin concentration placental parasitaemia cord parasitaemia Cord and mothers peripheral and placental blood collection on filter paper for PCR
Laboratory methods
- malaria diagnosis a thick and thin smear of fingerprick blood will be prepared from each subject Thin films will be fixed with methanol and stained with Giemsa in phosphate buffer pH 72 for 30 min and examined with a 100X oil immersion objective The parasite species will be determined on the thin film and the parasites densities evaluated on the thick film by counting the number of asexual Pfalciparum parasites against 200 leukocytes and expressed as number of parasites by microliter µl of blood assuming a standard leukocyte count of 8000µl At least 100 thick film fields will be examined to declare a slide negative
Blood collection on filter paper fingerprick blood will be collected on Whatmann 3MM chromatography filter paper About 80-100 µl blood will be directly blotted on the paper strips air dried and individually placed in plastic bag and conserved at room temperature in bottles containing silicagel
HB will be measured using a HemoCue portable photometer
Polymerase Chain Reaction PCR assays will be performed from blood on filter papers using the methods described by Jelinek et al 1999 for resistance to antifolates and by Djimde et al2001 for resistance to CQ
Drug efficacy assessment in pregnant women
The subjects will be recruited at ANC and adult outpatient units of the health facility Those who meet the inclusion criteria will be selected and requested to participate oral informed consent and then randomly allocated to CQ or SP treatment
Inclusion criteria
primi or secundigravidae from 12 to 24 weeks of gestation
pregnant women without at risk pregnancy
axillary body temperature 375C and 395C
no clinical sign of severe malaria
mono infection of P falciparum with a density 2000 trophozoites µl of blood
no sign of other febrile disease
staying in a neighbouring district or village
Exclusion criteria
severe malaria
any other febrile disease
previous side effects to CQ or SP consumption
loss to follow up
Inclusion and follow-up procedures
Enrolled women will be recorded with date identity number name age profession address temperature body weight parasitaemia haemoglobin concentration treatment follow-up temperatures parasitaemia and Hb other observations and results of the test Every subject will be asked to come at precise dates for follow up Those lost of follow up will be actively searched for the next day
Methods
The WHO 28 days assessment of therapeutic efficacy of antimalarials drugs for uncomplicated falciparum malaria in areas with intense transmission protocol will be used adapted to pregnant women
Data handling and statistical analysis All data will be recorded in pre-designed and tested questionnaires andor registers Then they will be progressively entered cleared checked and analysed using SPSS software
For the comparative randomized trial a general analysis will aim to describe the study samples through the calculation of variables means eg age parity parasite density haemoglobin concentrations birthweight the frequency of some clinical data as malaria attacks clinical results delivery outcomes mutations profiles
Then a comparative analysis will compare the proportions of main variables between the different treatment groups peripheral placenta and cord blood parasitaemia LBW prevalence of resistant strains mutations profiles clinical and parasitological responses using the chi-square test The means birthweight haemoglobin concentrations and number of clinical attacks will be compared between groups by t-test and one way analysis of variance Stratified or multivariate analysis tests will be used when necessary
Specific objectives
To investigate the effects of weekly CQ intermittent presumptive treatment with CQ and with SP on placental peripheral and cord parasitaemia and on P falciparum resistance status in primigravidae and secundigravidae
To determine the relationships between carriage of P falciparum resistant strains and malaria morbidity attacks and anaemia during pregnancy
To determine the clinical and parasitological efficacy of CQ and SP in primigravidae and secundigravidae
MATERIAL AND METHODS
The study will be conducted in a peripheral health centre of Ouagadougou Burkina Faso West Africa
The largest part of the country is tropical savannah with a rainy season from June to October average rainfall 1000 mm per year mean temperature 25C a cold dry season from November to February min temp 15C and a hot dry season from March to May Malaria transmission is seasonal June to Decemberand the major mosquito vectors are A gambiae A funestus and A arabiensis Malaria morbidity represents 30 to 50 of febrile illnesses and is the most frequent reason for health centres attendance and hospitals admissionSince its first notification in 1986 P falciparum resistance to CQ increased slowly with a considerable variation in space and time and resistance to SP has remained low CQ clinical failures are in general less than 20 in 6-59 months children and parasitological resistance is around 30 Malaria prevention in pregnancy is given as weekly 300 mg CQ following a presumptive initial treatment as recommended by the national malaria control programme MOH ANC services in health centres provide pregnant women with CQ and haematinics The health centre Centre médical Paul VI is a peri-urban health facility of Ouagadougou It comprises general outpatient consultation service paediatric and maternity wards and a laboratoryPatients come from the peri-urban districts and the neighbouring villages
Study design
a Comparative randomized trial
Three groups will be studied Pregnant women primigravidae and secundigravidae from 12 to 24 weeks of pregnancy will be randomly assigned using random numbers lists to treatment groups A to C as defined below
Group A pregnant women receiving weekly 300 mg CQ prophylaxis after a curative dose 10mgkg at days 1 and 2 5mgkg at day 3 at the first visit
Group B pregnant women receiving a presumptive CQ treatment at the 2nd and 3rd trimester of pregnancy 10mgkg at days 1 and 2 5mgkg at day 3
Group C pregnant women receiving a presumptive SP treatment at the 2nd and 3rd trimester of pregnancy 25mg sulfadoxine 125mg pyrimethaminekg in a single dose
Another group composed of primiparous and secundiparous women who are not part of the study and who come to deliver at the health centre group D and who have not received chloroquine prophylaxis during pregnancy will be considered as reflecting the normal situation and act as a control group These women will only be included during the first three months of the study
At inclusion
1 personal information anthropometric measures clinical data and obstetrical history will be recorded
2 fingerprick blood will be collected for a thick and a thin blood smear Hb and on filter paper for subsequent PCR tests
3 Treatment The single dose of SP and the 3 days of CQ treatment will be administered supervised by the research team
Study participants will be invited to come to the follow up visits or any time they feel sick or need health services
Follow-up visits at the beginning of second and third trimester will include
1 a clinical and parasitological examination The health events since the previous visit will be recorded Hb
2 providing chemoprophylaxis or treatment in accordance with the treatment group
At delivery the following data will be recorded
1 delivery outcomes birth weight mode of delivery APGAR score
2 mothers peripheral blood for thick blood smear Hb and filter paper for PCR
3 placental blood for thick blood smear and collection on filter paper for PCR
4 cord blood for thick blood smear If positive blood will be collected on filter paper for PCR
bClinical trial for the assessment of clinical and parasitological efficacy of CQ and SP in pregnant women
Primigravidae and secundigravidae women presenting with an uncomplicated malaria attack will be randomly treated with CQ or SP and regularly followed up to assess clinical and parasitological efficacy A molecular analysis of parasite gene mutations conferring resistance to chloroquine PfCRT and antifolates DHFR DHPS will be performed
The patients will randomly assigned to treatment with either CQ or SP They will then be followed-up during 28 days in accordance with WHO protocol The follow up criteria are clinical body temperature and parasitological peripheral parasitaemia
Sample size
a Comparative randomized trial Considering the prevalence of placenta parasitaemia to be 35 in pregnant women who do not get prophylaxis 24 in women with weekly CQ prophylaxis 15 in women with intermittent presumptive treatment with CQ and 5 in women with intermittent presumptive treatment with SP and using a significance level of 5 a power of 80 and 20 drop-out each group should include 200 subjects
a Drug efficacy assessment in pregnant women Considering the proportion of pregnant women with clinical failures to be 10-15 for chloroquine and using a significance level of 5 a power of 80 and 20 drop-out a sample of 42 subjects should be included
Methods
1 Comparative randomized trial
Pregnant women will be recruited at the ANC unit of the health facility if fulfilling the following inclusion criteria and give oral informed consent
Inclusion criteria
primi or secundigravidae - seen between 12th and 24th weeks of gestation
with a non at risk pregnancy multiple pregnancy obstetric misproportions previous caesarean high blood pressure diabetes clinical signs of AIDS
staying in a neighbouring district or village
ability to come for follow-up and delivery
Exclusion criteria
At risk pregnancy
Severe systemic disease
Wish to withdraw from participation
Inclusion and follow-up procedures
The study aims and procedures will be clearly explained to those meeting the inclusion criteriaEnrolled women will be registered and a personal health file created to be filled at enrolment follow-up and delivery Each woman will be given a health record booklet to be presented at any visit The following information will be recorded
At enrolment
Identity number date and treatment group
Name age profession place of residence address and name of husband and other close relatives
Clinical history axillary temperature body weight height clinical anaemia jaundice splenomegaly hepatomegaly stethoscopy of heart and lungs blood pressure and peripheral oedema
Obstetrical data date LMP uterine size presumed delivery date foetal heart beat previous pregnancy outcome normal abortion stillbirth complications during pregnancy and labour
Biological data Plasmodium species and density Hb filter paper blood for PCR
Follow-up
Clinical follow-up fever episodes diseases other treatments
Obstetrical follow-up uterine height foetal heart beat
Biological follow-up Plasmodium species and density Hb filter paper blood for PCR
Delivery
- Date and time labor started midwifes name
Clinical data body temperature blood pressure and clinical examination
Mode of delivery APGAR scores and birthweight
Biological data mothers peripheral parasitaemia haemoglobin concentration placental parasitaemia cord parasitaemia Cord and mothers peripheral and placental blood collection on filter paper for PCR
Laboratory methods
- malaria diagnosis a thick and thin smear of fingerprick blood will be prepared from each subject Thin films will be fixed with methanol and stained with Giemsa in phosphate buffer pH 72 for 30 min and examined with a 100X oil immersion objective The parasite species will be determined on the thin film and the parasites densities evaluated on the thick film by counting the number of asexual Pfalciparum parasites against 200 leukocytes and expressed as number of parasites by microliter µl of blood assuming a standard leukocyte count of 8000µl At least 100 thick film fields will be examined to declare a slide negative
Blood collection on filter paper fingerprick blood will be collected on Whatmann 3MM chromatography filter paper About 80-100 µl blood will be directly blotted on the paper strips air dried and individually placed in plastic bag and conserved at room temperature in bottles containing silicagel
HB will be measured using a HemoCue portable photometer
Polymerase Chain Reaction PCR assays will be performed from blood on filter papers using the methods described by Jelinek et al 1999 for resistance to antifolates and by Djimde et al2001 for resistance to CQ
Drug efficacy assessment in pregnant women
The subjects will be recruited at ANC and adult outpatient units of the health facility Those who meet the inclusion criteria will be selected and requested to participate oral informed consent and then randomly allocated to CQ or SP treatment
Inclusion criteria
primi or secundigravidae from 12 to 24 weeks of gestation
pregnant women without at risk pregnancy
axillary body temperature 375C and 395C
no clinical sign of severe malaria
mono infection of P falciparum with a density 2000 trophozoites µl of blood
no sign of other febrile disease
staying in a neighbouring district or village
Exclusion criteria
severe malaria
any other febrile disease
previous side effects to CQ or SP consumption
loss to follow up
Inclusion and follow-up procedures
Enrolled women will be recorded with date identity number name age profession address temperature body weight parasitaemia haemoglobin concentration treatment follow-up temperatures parasitaemia and Hb other observations and results of the test Every subject will be asked to come at precise dates for follow up Those lost of follow up will be actively searched for the next day
Methods
The WHO 28 days assessment of therapeutic efficacy of antimalarials drugs for uncomplicated falciparum malaria in areas with intense transmission protocol will be used adapted to pregnant women
Data handling and statistical analysis All data will be recorded in pre-designed and tested questionnaires andor registers Then they will be progressively entered cleared checked and analysed using SPSS software
For the comparative randomized trial a general analysis will aim to describe the study samples through the calculation of variables means eg age parity parasite density haemoglobin concentrations birthweight the frequency of some clinical data as malaria attacks clinical results delivery outcomes mutations profiles
Then a comparative analysis will compare the proportions of main variables between the different treatment groups peripheral placenta and cord blood parasitaemia LBW prevalence of resistant strains mutations profiles clinical and parasitological responses using the chi-square test The means birthweight haemoglobin concentrations and number of clinical attacks will be compared between groups by t-test and one way analysis of variance Stratified or multivariate analysis tests will be used when necessary
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