Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00146783 |
| Other study ID # |
ITCR5096 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2/Phase 3
|
| First received |
September 5, 2005 |
| Last updated |
January 11, 2017 |
| Start date |
June 2004 |
| Est. completion date |
February 2007 |
Study information
| Verified date |
January 2017 |
| Source |
London School of Hygiene and Tropical Medicine |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Ghana: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial Summary
In areas of stable transmission, pregnant women, especially during the first and second
pregnancies, have an increased susceptibility to Plasmodium falciparum malaria,
malaria-related anaemia and an increased risk of having low birthweight babies. Intermittent
Preventive Treatment in pregnancy(IPTp) with sulphadoxine-pyrimethamine has been shown to be
effective in reducing the effects of malaria in pregnancy. This has mainly been in areas of
perennial transmission and there is a need to study this effect in intense seasonal
transmission settings. The emergence and spread of resistance to SP is likely to undermine
its useful lifespan and it is important that other antimalarials that are safe and effective
are identified for use in IPTp. The options are however limited. Amodiaquine has been shown
to be effective in treatment of clinical cases of malaria, even in areas where chloroquine
resistance is prevalent, and its combination with SP has been associated with favourable
results. Both are affordable. However, there is limited data on their use in pregnancy. This
study aims to assess the efficacy of SP in an area of intense seasonal transmission, and
evaluate the safety and efficacy of amodiaquine and a combination of
sulphadoxine-pyrimethamine and amodiaquine as possible alternatives to SP for use as IPTp.
Description:
Background Pregnant women, particularly during the first and second pregnancy, have a high
risk of Plasmodium falciparum infection and these infections are often asymptomatic but lead
to maternal anaemia and low birth-weight. One approach to preventing malaria in pregnancy is
prompt effective management of clinical malaria. In areas of moderate and high transmission
however, peripheral parasitaemia is not a sensitive indicator as many women with placental
parasitaemia may not have peripheral parasitaemia. Another option is to administer full
curative doses of an effective antimalarial drug at predefined intervals during pregnancy
(IPTp) without screening for parasitaemia. The efficacy of IPTp has been studied mostly in
areas of high perennial transmission in Kenya and Malawi. IPTp has however been little
investigated in West Africa where transmission is often intense and highly seasonal. It may
not be appropriate to translate results between areas with different ranges of transmission
intensities across the sub-Saharan African region and there is a need to study the effect of
IPTp in highly seasonal intense transmission areas in West Africa.
IPTp with SP has been shown to be effective in reducing maternal anaemia, prevalence of
placental parasitaemia and the incidence of low birth weight. SP offers a reasonable
combination of ease of use and associated increased compliance, low cost, and relatively
good tolerance and safety. However, the useful therapeutic life (UTL) predicted for SP is
likely to be short, in part due to its prolonged half-life, causing a higher probability of
selecting resistant strains and consequent rapid development of resistance. The emergence
and spread of SP resistance will increasingly undermine this strategy, depleting the
currently available and affordable drugs usable for intervention during pregnancy. It is
therefore important that alternative antimalarials that are safe and effective in pregnancy
are identified.
Specific primary objective To assess and compare the efficacy of a combination of
sulphadoxine-pyrimethamine and amodiaquine, sulphadoxine-pyrimethamine or amodiaquine used
as IPTp, in reducing the incidence of anaemia(Hb<11g/dl) at weeks 34-36 among primigravidae
and secundigravidae.
Specific secondary objectives
To evaluate the effect of SP/AQ, SP or AQ on:
1. The mean birthweight of infants among primigravidae and secundigravidae
2. The incidence of clinical malaria during pregnancy among primigravidae and
secundigravidae
3. The prevalence of anaemia (Hb <11g/dl) at delivery among primigravidae and
secundigravidae
4. The prevalence of placental parasitaemia among women in their first or second
pregnancies delivering at health facilities or by trained TBAs
5. The prevalence of peripheral parasitaemia at weeks 34-36 among primigravidae and
secundigravidae
6. The prevalence of maternal peripheral parasitaemia at delivery among primigravidae and
secundigravidae
7. To determine the safety and tolerability of AQ, SP used alone and in combination, among
pregnant women of all parities
8. To determine the prevalence of molecular markers of resistance to AQ and SP among
pregnant women who have malaria parasitaemia at enrolment
9. To document the factors that influence women's attitude towards ANC attendance, use of
chemoprophylaxis and ITNs, and to determine what informs their choice to deliver at a
particular facility
STUDY SITE The study will be carried out in the Kassena-Nankana district of northern Ghana.
The residents are mainly subsistence farmers. There are two main seasons, a short wet season
from June to September, during which the transmission of Plasmodium species peaks and a long
dry season. The primary resource of the Navrongo Health Research Centre is a district-wide
surveillance system, the Navrongo Demographic Surveillance System (NDSS), a longitudinal
population registration system that is updated every 90 days. The district has 4 health
centres, 3 clinics and a 140-bed hospital that serves as a referral centre. Information
collated for the year 2002 in the Kassena-Nankana district indicated that out of an expected
6050 pregnancies, 95% registered for ANC, the average number of visits being 2.7. There were
2173(36%) supervised deliveries, 1279 of these at health facilities and 894 by trained TBAs.
794 out of 2405(33%) pregnant women had haemoglobin levels less than 10g/dl at registration.
STUDY POPULATION Pregnant women between 16 -32 weeks gestation attending antenatal care
clinics at the district hospital or any of the four main health centres in the district will
be eligible to join the study. The main endpoints will be assessed in primigravidae and
secundigravidae however safety data will be collected for all women.
STUDY DESIGN The study will be carried out in two phases, a pre-intervention phase which
will document women's knowledge, attitudes and practices on antenatal care, chemoprophylaxis
and use of insecticide treated bednets and factors that influence their choice of where to
deliver. The second phase, which is the intervention, will be a three-arm randomized blinded
controlled trial.
Intervention study - Enrolment procedure The study will be explained to women as a group
before each day's ANC activities begin. In order not to interfere with the routine ANC
activities women who may want to be recruited will then proceed to the study team after
their routine ANC care. After obtaining informed consent, socio-demographic information, an
obstetric history including previous ANC attendances during current pregnancy, a history of
any illness in the past week, and information on bed net use will be collected. Gestational
age will be obtained from the ANC card as assessed by the midwife. Anthropometric indices
measured will be weight, height and mid-upperarm circumference. The blood pressure and
axillary temperature will also be measured. Fingerstick blood sample will be drawn for
haemoglobin testing, malaria thick blood smear and filter paper samples, after which each
woman will be assessed for eligibility. Subjects will be randomized individually to receive
the study drugs. The code on the envelope will be written on all the study forms and
samples. The subject's name, address and date of first dosing will be noted on the envelope,
to ensure that each woman receives the right regimen over the three-day period and also
during subsequent doses of IPTp. To ensure compliance, all doses will be supervised either
at the health facility, or through home visits (on Days 1 and 2). Women will receive between
one and three doses of the drugs, depending on gestational age at recruitment, thus women
recruited at 16 - 19 weeks will receive three doses, those recruited at 20 -26 weeks, two
doses and those recruited from 27 -32weeks, one dose. The interval between dosing schedules
will be 8 weeks, however the minimum interval allowed will be 4 weeks.
All women will be encouraged to deliver at a health facility or by a trained traditional
birth attendant, and they will be given an identification card to take to the health
facility so that the necessary samples can be taken and labelled adequately during delivery.
These identification cards will also bear a note that the woman may have received AQ, SP or
a combination as IPTp and should therefore not be given those drugs for clinical malaria, to
avoid women being given repetitive doses within short intervals of time. Such women will be
given Quinine 10mg/kg 8 hourly for 7days as recommended by the national treatment
guidelines.
Assessment of drug tolerance and adverse drug reactions All women will be visited at home
between Days 7 and 10 to look for any adverse events due to the study drugs. They will be
advised to report to a health facility if they should experience any untoward effect of the
drugs prior to, or after this home visit. The frequency and severity of spontaneous and
elicited adverse events will be recorded. In the light of the information obtained, the
association between the event and any of the study drugs will be judged as per the WHO
guidelines52. All serious and adverse events will be reported to the DSMB immediately, and
followed up with a written report which will fully document the event, and any available
laboratory information or clinical data, will be included in the report.
Follow-up At subsequent visits for IPTp and at weeks 34 -36, a simple questionnaire will be
administered to assess the presence of malaria symptoms, potential side effects of the study
drugs since the last assessment, and bednet use. To ensure that women complete subsequent
doses of IPTp, lists of women due for second or third doses will be computer-generated, and
they will be reminded at least a week before the next dose is due to attend the ANC. At 34
-36 weeks blood samples will be taken to assess for haemoglobin levels (Hb) and peripheral
parasitaemia. Women with severe anaemia (Hb levels <7g/dl) will be referred to the hospital
for further investigations and management. Women who do not turn up at the ANC will be
followed up at home to collect the blood sample. Blood slides from symptomatic women will be
read immediately and women found to have parasitaemia will be given Quinine 10mg/kg 8 hourly
for 7 days as per national treatment guidelines.
Delivery Women delivering at the hospital will have bloodsmears made from a fingerprick, and
maternal side of the placenta, and have Hb level assessed. Women delivering at the health
centre will have placental blood smears, and a peripheral blood smear taken. Those delivered
by TBAs will have the placental smear taken.
Blood samples for haemoglobin estimation for women delivering at the health centre or by
TBAs will be taken at home within 7 days of delivery. Assessment of Hb will be carried out
on women who delivered spontaneously without any complications such as post-partum
haemorrhage at the hospital on day of delivery to 7days post delivery, to construct a
nomogram which would be used to estimate the haemoglobin levels at delivery for women who
delivered at the health centre or by TBA who could not have an Hb done on day of delivery
for logistic reasons.
All infants delivered at the hospital or health centre will be weighed and gestational age
assessed by a modification of Dubowitz's examination within 24 hours of delivery53. To
ensure that birthweights of infants delivered at home are taken within seven days of
delivery, a list of women with gestation of 34 weeks or more will be generated according to
area of residence. This would be given to Community Key Informants (CKI) who would be
contacted weekly by field staff for information on those who were delivered by TBAs or at
home. A follow-up will then be made to take the weight of the babies. Mothers will be
encouraged to inform CKIs soon after delivery. The TBAs will be asked to inform CKIs
whenever they delivered a study subject, so that the samples can be collected.
Infants for whom the Dubowitz score is obtained will be classified as follows:
Premature -LBW : gestational age is <37weeks and birthweight is <2500g IUGR-LBW: gestational
age is ≥ 37weeks and birthweight is <2500g Normal birthweight : birthweight is ≥ 2500g
Withdrawal from study A withdrawal shall be any enrolled subject who does not complete the
study as planned. This may be due to (a) withdrawal of consent, (b) reaction attributable to
any of the study drugs or (c) termination of pregnancy (abortions or miscarriages). A
withdrawal form shall be filled for such persons, indicating reasons for withdrawal, and
they will be followed up for outcome measures, unless they decline to give consent.
