Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00140517 |
| Other study ID # |
HSR/DD/677-01/DG-CM/624-02 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
August 31, 2005 |
| Last updated |
January 11, 2017 |
| Start date |
October 2002 |
| Est. completion date |
March 2008 |
Study information
| Verified date |
January 2017 |
| Source |
London School of Hygiene and Tropical Medicine |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Burkina Faso: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial 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.
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 > 25°C), a cold dry season
from November to February, (min. temp. 15°C) and a hot dry season from March to May. Malaria
transmission is seasonal (June to December)and 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 admission.Since it's
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
laboratory.Patients 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
(10mg/kg at days 1 and 2 +5mg/kg at day 3) at the first visit ;
- Group B : pregnant women receiving a presumptive CQ treatment at the 2nd and 3rd
trimester of pregnancy (10mg/kg at days 1 and 2 +5mg/kg at day 3);
- Group C: pregnant women receiving a presumptive SP treatment at the 2nd and 3rd
trimester of pregnancy (25mg sulfadoxine + 1,25mg pyrimethamine/kg 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. mother's 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
b)Clinical 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 criteria.Enrolled 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, midwife's name.
- Clinical data: body temperature, blood pressure, and clinical examination.
- Mode of delivery, APGAR scores, and birthweight.
- Biological data: mother's peripheral parasitaemia, haemoglobin concentration,
placental parasitaemia, cord parasitaemia. Cord and mother's 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 7.2) 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
P.falciparum parasites against 200 leukocytes and expressed as number of parasites
by microliter (µl) of blood assuming a standard leukocyte count of 8000/µl. 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 al.2001 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 > 37.5°C and < 39.5°C
• 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 and/or 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 (e.g. 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.
